LipidsNATURE OF LIPIDSNATURE OF LIPIDS

�� Lipids have a hydrophobic nature Lipids have a hydrophobic nature because of the predominance of because of the predominance of hydrocarbon chains (hydrocarbon chains (——CHCH22——CHCH22hydrocarbon chains (hydrocarbon chains (——CHCH22——CHCH22——CHCH22——) in their structure. ) in their structure.

�� They areThey are insoluble or only poorly insoluble or only poorly soluble in water, but readily soluble in water, but readily soluble in nonpolar solvents such soluble in nonpolar solvents such as ether and benzene.as ether and benzene.

Some common classifications of lipids Some common classifications of lipids and their general biologic functionsand their general biologic functions

Lipid Primary Functions

Fatty acids Energy sources, biosynthetic precursors

Triacylglycerols Storage, transportTriacylglycerols Storage, transport

Phosphoglycerides Membrane components

Ketone bodies Energy sources

Sphingolipids Membrane components

Eicosanoids Modulators of physiologic activity

Cholesterol Membrane component

Steroid hormones Modulators of physiologic activity

CommonCommon

NameName

SystematicSystematic NameName NoNo..

CarbonCarbon

AtomsAtoms

NoNo..

DoubleDouble

BondsBonds

MelMel..

PointPoint

((°°C)C)

LauricLauric DodecanoicDodecanoic 1212 00 4343..55

MyristicMyristic TetradecanoicTetradecanoic 1414 00 5454..44

PalmiticPalmitic HexadecanoicHexadecanoic 1616 00 6262..88PalmiticPalmitic 1616 00 6262..88

StearicStearic OctadecanoicOctadecanoic 1818 00 6969..66

PalmitoleicPalmitoleic ciscis--∆∆99--HexadecenoicHexadecenoic 1616 11 11..00

OleicOleic ciscis--∆∆99--OctadecenoicOctadecenoic 1818 11 1313..00

LinoleicLinoleic allall ciscis--∆∆99,,∆∆1212--OctadecadienoicOctadecadienoic 1818 22 --1111..00

LinolenicLinolenic allall ciscis--∆∆99,,∆∆1212,,∆∆1515--OctadecatrienoicOctadecatrienoic 1818 33 --1111..22

ArachidonicArachidonic allall ciscis--∆∆55,,∆∆88,,∆∆1111,,∆∆1414--EicosatetraenoicEicosatetraenoic 2020 44 --4949..55

Saturated fatty acids Saturated fatty acids do not have do not have double bonds in the chaindouble bonds in the chain

–– Nomenclature. The systematic Nomenclature. The systematic namename gives the number of carbons, gives the number of carbons, with the suffix with the suffix --anoic anoic appended. appended. Palmitic acid, for example, has 16 Palmitic acid, for example, has 16 Palmitic acid, for example, has 16 Palmitic acid, for example, has 16 carbons and has the systematic name carbons and has the systematic name hexadecanoic acid.hexadecanoic acid.

–– Structure. The general formulaStructure. The general formula of of saturated fatty acids is CHsaturated fatty acids is CH33——(CH(CH22)n)n--COOH, where COOH, where n n is the number of is the number of methylene groups between the methyl methylene groups between the methyl and carboxyl carbons.and carboxyl carbons.

Unsaturated fatty acids Unsaturated fatty acids have one have one or more double bondsor more double bonds

�� In naturally occurring fatty acids, these bonds are In naturally occurring fatty acids, these bonds are always in a always in a ciscis as opposed to a as opposed to a trans trans configuration configuration (i.e., the single hydrogens bonded to each carbon (i.e., the single hydrogens bonded to each carbon are oriented in the same direction). are oriented in the same direction).

�� The most commonly used system for designating The most commonly used system for designating the position of double bonds in an unsaturated fatty the position of double bonds in an unsaturated fatty the position of double bonds in an unsaturated fatty the position of double bonds in an unsaturated fatty acid is the delta (acid is the delta (∆∆) numbering system. ) numbering system. –– Numbering system.Numbering system. The terminal carboxyl carbon is The terminal carboxyl carbon is

designated Cdesignated C--1, and the double bond is given the number 1, and the double bond is given the number of the carbon on the carboxyl side of the double bond. For of the carbon on the carboxyl side of the double bond. For example, palmitoleic acid, which has 16 carbons and a example, palmitoleic acid, which has 16 carbons and a double bond between Cdouble bond between C--9 and C9 and C--10, is designated 16:1:10, is designated 16:1:∆∆9, 9, or 16:1:9. or 16:1:9.

–– The The systematic namesystematic name gives the number of carbon atoms, gives the number of carbon atoms, number of double bonds (unless it has only one), and bears number of double bonds (unless it has only one), and bears the suffix the suffix --enoicenoic. Thus, linoleic acid, with 18 carbons and . Thus, linoleic acid, with 18 carbons and two two ciscis double bonds, is double bonds, is ciscis--∆∆9,9,∆∆1212--octadecadienoic acid.octadecadienoic acid.

Source of fatty acidsSource of fatty acids

�� 1. Nonessential fatty acids. 1. Nonessential fatty acids. Nonessential Nonessential fatty acids can be synthesized from products fatty acids can be synthesized from products of glucose oxidation and do not, therefore, of glucose oxidation and do not, therefore, have to be included in the diet.have to be included in the diet.have to be included in the diet.have to be included in the diet.

�� 2. Essential fatty acids. 2. Essential fatty acids. Fatty acids of the Fatty acids of the linoleic (18:2:linoleic (18:2:∆∆9,129,12) and linolenic ) and linolenic (18:3:(18:3:∆∆9,12,159,12,15) families must be obtained ) families must be obtained from the diet.from the diet.

Physical propertiesPhysical properties

�� Fatty acids are detergentFatty acids are detergent--like because of like because of their their amphipathic natureamphipathic nature. . They have nonThey have non--polar (CHpolar (CH33) and polar () and polar (——COOH) ends. In COOH) ends. In biphasic systems, they orient with the polar biphasic systems, they orient with the polar end associated with water and the nonpolar end associated with water and the nonpolar end associated with water and the nonpolar end associated with water and the nonpolar end associated with the hydrophobic phase.end associated with the hydrophobic phase.

�� The melting point of fatty acids is related to The melting point of fatty acids is related to chain length and degree of unsaturation. chain length and degree of unsaturation. The longer the chain length, the higher the The longer the chain length, the higher the melting point; the greater the number of melting point; the greater the number of double bonds, the lower the melting point.double bonds, the lower the melting point.

Triacylglycerols (triglycerides)Triacylglycerols (triglycerides)

�� Structure.Structure. Triacylglycerols are Triacylglycerols are triesters of glycerol and three fatty triesters of glycerol and three fatty acids.acids.acids.acids.

FunctionFunction�� Fatty acids are converted to triacylglycerols for transport Fatty acids are converted to triacylglycerols for transport

between tissues and for storage of metabolic fuel.between tissues and for storage of metabolic fuel.–– The main stores of metabolic fuel in humans are the fat deposits The main stores of metabolic fuel in humans are the fat deposits

in fat cells in fat cells (adipocytes).(adipocytes). These serve longThese serve long--term needs for term needs for metabolic fuel.metabolic fuel.�� Triacylglycerols have two major advantages over other forms of Triacylglycerols have two major advantages over other forms of

metabolic fuel. metabolic fuel. –– Triacylglycerols provide a concentrated form of fuel because their Triacylglycerols provide a concentrated form of fuel because their

complete combustion to carbon dioxide (COcomplete combustion to carbon dioxide (CO22) and water releases 9 ) and water releases 9 kcal/g as opposed to 4 kcal/g for carbohydrate.kcal/g as opposed to 4 kcal/g for carbohydrate.

–– Because they are water insoluble, triacylglycerols present no osmotic Because they are water insoluble, triacylglycerols present no osmotic –– Because they are water insoluble, triacylglycerols present no osmotic Because they are water insoluble, triacylglycerols present no osmotic problems to the cell when stored in large amounts.problems to the cell when stored in large amounts.

�� LipolysisLipolysis involves the involves the hydrolysis of triacylglycerols hydrolysis of triacylglycerols to free glycerol and free fatty acidsto free glycerol and free fatty acids (also known as (also known as nonesterified fatty acids)nonesterified fatty acids) with both products leaving with both products leaving the adipocyte. The appearance of fatty acids in the blood the adipocyte. The appearance of fatty acids in the blood during fasting is due to the mobilization of fat stores by during fasting is due to the mobilization of fat stores by this process.this process.–– Utilization of fatty acidsUtilization of fatty acids. . Fatty acids are used by most tissues, Fatty acids are used by most tissues,

except the brain, as a metabolic fuel.except the brain, as a metabolic fuel.–– Utilization of glycerolUtilization of glycerol. . Glycerol is used by the liver as a Glycerol is used by the liver as a

substrate for gluconeogenesis.substrate for gluconeogenesis.

Ketone bodiesKetone bodies

Ketone bodies, Ketone bodies, which are formed from fatty which are formed from fatty

C O

CH3

CH3

C O

CH3

CH2

C

HO

O

CH OH

CH3

CH2

C

HO

O

�� Ketone bodies, Ketone bodies, which are formed from fatty which are formed from fatty acids and carbohydrates, include acetone, acids and carbohydrates, include acetone, acetoacetate, and acetoacetate, and ββ--hydroxybutyrate.hydroxybutyrate.–– Ketone bodies are synthesized in liver mitochondria and Ketone bodies are synthesized in liver mitochondria and

released into the blood for use as metabolic fuel by other released into the blood for use as metabolic fuel by other tissues. tissues. The liver does not use ketone bodiesThe liver does not use ketone bodies..

–– Levels of synthesis are high when the rate of fatty acid Levels of synthesis are high when the rate of fatty acid oxidation is high and carbohydrate utilization is low. This oxidation is high and carbohydrate utilization is low. This occurs during fasting, starvation, untreated diabetes, and occurs during fasting, starvation, untreated diabetes, and prolonged alcohol abuse.prolonged alcohol abuse.

KetoacidosisKetoacidosis

�� Ketoacidosis Ketoacidosis is an imbalance of blood pH caused is an imbalance of blood pH caused by the excessive accumulation of acetoacetate or by the excessive accumulation of acetoacetate or ββ--hydroxybutyrate, which are weak acids.hydroxybutyrate, which are weak acids.–– KetosisKetosis refers to refers to ketonuriaketonuria (high urine levels of ketone (high urine levels of ketone bodies) and bodies) and ketonemiaketonemia (high blood levels of ketone (high blood levels of ketone bodies) and bodies) and ketonemiaketonemia (high blood levels of ketone (high blood levels of ketone bodies).bodies).

–– During starvation, ketone bodies are the only source of During starvation, ketone bodies are the only source of fuel, so they are consumed by the body, and there is no fuel, so they are consumed by the body, and there is no excess to accumulate. In contrast, in untreated diabetes, excess to accumulate. In contrast, in untreated diabetes, blood levels of ketone bodies may become high enough to blood levels of ketone bodies may become high enough to produce lifeproduce life--threatening ketoacidosisthreatening ketoacidosis

PHOSPHOLIPIDSPHOSPHOLIPIDS

�� are the major lipid constituents of are the major lipid constituents of cellular membranes. cellular membranes.

�� They comprise approximately 40% of They comprise approximately 40% of �� They comprise approximately 40% of They comprise approximately 40% of the lipids in the erythrocyte membrane the lipids in the erythrocyte membrane and more than 95% of the lipids in the and more than 95% of the lipids in the inner mitochondrial membrane. inner mitochondrial membrane.

PhosphoglyceridesPhosphoglycerides

�� are triesters of glycerolare triesters of glycerol--33--phosphate in which two esters phosphate in which two esters have been formed between the have been formed between the two hydroxyl groups and fatty two hydroxyl groups and fatty

CH2 O C

O

O

R1

two hydroxyl groups and fatty two hydroxyl groups and fatty acid side chains (Racid side chains (R11 and Rand R22), ), and a third ester has been and a third ester has been formed between the phosphate formed between the phosphate group and a hydroxylgroup and a hydroxyl--containing compound, X.containing compound, X.

CH

CH2

O

O P

C

O

O

R2

O

O-

X

Classification of phosphoglyceridesClassification of phosphoglycerides

�� Phosphoglycerides include the following Phosphoglycerides include the following compounds:compounds:–– PhosphatidylcholinePhosphatidylcholine (lecithin)(lecithin)–– PhosphatidylethanolaminePhosphatidylethanolamine (a cephalin)(a cephalin)–– PhosphatidylethanolaminePhosphatidylethanolamine (a cephalin)(a cephalin)–– PhosphatidylserinePhosphatidylserine (a cephalin)(a cephalin)–– PhosphatidylinositolPhosphatidylinositol

–– Cardiolipin,Cardiolipin, which comprises approximately which comprises approximately 20% of the lipids of the inner mitochondrial 20% of the lipids of the inner mitochondrial membranemembrane

Characteristics of Characteristics of phosphoglyceridesphosphoglycerides�� Phosphoglycerides are the most polar lipids Phosphoglycerides are the most polar lipids and are and are amphipathicamphipathic, , possessing possessing both both hydrophilic and hydrophobic groupshydrophilic and hydrophobic groups. . They inhabit transition regions between They inhabit transition regions between They inhabit transition regions between They inhabit transition regions between aqueous and nonaqueous phases.aqueous and nonaqueous phases.

�� Phosphoglycerides are Phosphoglycerides are amphoteric, amphoteric, bearingbearing both negatively and positively both negatively and positively charged groups.charged groups.

�� SPHINGOLIPIDSSPHINGOLIPIDS are present in are present in nearly all human tissues. The greatest nearly all human tissues. The greatest concentration of sphingolipids is found concentration of sphingolipids is found concentration of sphingolipids is found concentration of sphingolipids is found in the central nervous system (CNS), in the central nervous system (CNS), particularly in white matterparticularly in white matter

SPHINGOLIPIDSSPHINGOLIPIDS

�� Function.Function. Sphingomyelin is the major Sphingomyelin is the major phospholipid component of membranes in phospholipid component of membranes in neural tissues.neural tissues.

�� Structure.Structure. Sphingomyelin, which is derived Sphingomyelin, which is derived �� Structure.Structure. Sphingomyelin, which is derived Sphingomyelin, which is derived from the amino alcohol, sphingosine, is the from the amino alcohol, sphingosine, is the only sphingolipid that contains phosphate only sphingolipid that contains phosphate and has no sugar moiety. It is formed from and has no sugar moiety. It is formed from ceramideceramide, , which is the which is the core structurecore structure of of naturally occurring sphingolipids, including naturally occurring sphingolipids, including the glycosphingolipids.the glycosphingolipids.

Glycosphingolipids Glycosphingolipids are are sphingolipids that contain sphingolipids that contain carbohydrate moietiescarbohydrate moieties�� CerebrosidesCerebrosides are ceramide monohexosides, the most are ceramide monohexosides, the most important being important being galactocerebroside and galactocerebroside and glucocerebroside.glucocerebroside. Cerebrosides are found in neural Cerebrosides are found in neural tissue membranes, particularly the myelin sheath.tissue membranes, particularly the myelin sheath.SulfatidesSulfatides are Cerebrosides that contain sulfated are Cerebrosides that contain sulfated �� SulfatidesSulfatides are Cerebrosides that contain sulfated are Cerebrosides that contain sulfated sugars. sugars. ββββββββ--SulfogalactocerebrosideSulfogalactocerebroside accounts for accounts for approximately 15% of the lipids in white matter of the approximately 15% of the lipids in white matter of the brain.brain.

�� GlobosidesGlobosides are ceramide oligosaccharides that contain are ceramide oligosaccharides that contain two or more sugar molecules, most often galactose, two or more sugar molecules, most often galactose, glucose, or Nglucose, or N--acetylgalactosamine, attached to acetylgalactosamine, attached to ceramide. They are found in serum, the spleen, the ceramide. They are found in serum, the spleen, the liver, and erythrocytes. For example, liver, and erythrocytes. For example, lactosylceramidelactosylceramide is found in erythrocyte membranesis found in erythrocyte membranes

GangliosidesGangliosides

Nature Nature �� Gangliosides are glycosphingolipids that contain one or more Gangliosides are glycosphingolipids that contain one or more

neuraminic acid residues, usually as the Nneuraminic acid residues, usually as the N--acetyl derivative [i.e., acetyl derivative [i.e., NN--acetylneuraminic acidacetylneuraminic acid (NANA)], which is (NANA)], which is sialic acid. sialic acid. They are They are found in high concentration in ganglion cells of the CNS and in lower found in high concentration in ganglion cells of the CNS and in lower concentration in the membranes of most cells.concentration in the membranes of most cells.concentration in the membranes of most cells.concentration in the membranes of most cells.

NomenclatureNomenclature�� The letter G is used to denote a ganglioside, with M, D, T, or Q to The letter G is used to denote a ganglioside, with M, D, T, or Q to

indicate, respectively, monoindicate, respectively, mono--, di, di--, tri, tri--, or quatrosialic acid contents. , or quatrosialic acid contents. Numerical subscripts are based on their chromatographic migration. Numerical subscripts are based on their chromatographic migration. For example:For example:–– GM1 = GalGM1 = Gal--(N(N--AcGal)AcGal)--GalGal--GlcGlc--CerCer–– GM2 = (NGM2 = (N--AcGal)AcGal)--GalGal--GlcGlc--CerCer–– GM3 = GalGM3 = Gal--GlcGlc--CerCer

where where Cer Cer = ceramide, = ceramide, Glc = Glc = glucose, glucose, Gal = Gal = galactose, and galactose, and NN--AcGal AcGal = N= N--acetylgalactosamine.acetylgalactosamine.

�� For example, the GM2 ganglioside is:For example, the GM2 ganglioside is:(N-AcGal)-Gal-Glc-Cer

NANA

SphingolipidosesSphingolipidoses are inherited genetic disorders referred to are inherited genetic disorders referred to as as lipid storage diseases, lipid storage diseases, in which there is a deficiency of an in which there is a deficiency of an enzyme that is involved in the normal catabolism of a enzyme that is involved in the normal catabolism of a particular sphingolipidparticular sphingolipid. . This results in the intracellular This results in the intracellular accumulation of that lipid to harmful levels.accumulation of that lipid to harmful levels.

Disease Lipid Accumulated Enzyme

Deficiency

Primary Organ

Affected

Niemann-Pick Sphingomyelin Sphingomyelinase Brain, liver,

spleenspleen

Gaucher's Glucocerebroside β-Glucosidase Brain, liver,

spleen

Krabbe's Galactocerebroside β-Galactosidase Brain

Metachromatic

leukodystrophy

β-Sulfogalactocerebroside Sulfatide sulfatase Brain

Fabry's Ceramide trihexoside α-Galactosidase Kidneys

Tay-Sachs Ganglioside GM2 Hexosaminidase A Brain

STEROIDSSTEROIDS

�� STEROIDSSTEROIDS are lipids that contain four are lipids that contain four fused carbon rings that form the fused carbon rings that form the cyclopentanoperhydrophenanthrene cyclopentanoperhydrophenanthrene steroid nucleus.steroid nucleus.

CholesterolCholesterol is the major is the major sterolsterol in the human body. Sterols in the human body. Sterols are a class of steroids characterized by a hydroxyl group are a class of steroids characterized by a hydroxyl group at carbon 3, and an aliphatic chain of at least eight at carbon 3, and an aliphatic chain of at least eight carbons at Ccarbons at C--1717

�� Cholesterol is a Cholesterol is a structural componentstructural component of cell of cell membranes and plasma lipoproteins.membranes and plasma lipoproteins.

�� ItIt is the is the precursorprecursor from which steroid hormones from which steroid hormones and bile acids are synthesized.and bile acids are synthesized.and bile acids are synthesized.and bile acids are synthesized.

Vitamin DThe binding of vitamin D to receptor turns on the gene responsible

for the synthesis of a Ca2+ binding protein

Absence in diet, or insufficient sunlight, leads to rickets

Typically vitamins are

included in various foodsincluded in various foods

such as bread and milk.

Vitamin D2 is added to

milk and butter

Purification of Lipids from Biological Samples Purification of Lipids from Biological Samples

Lipid metabolism. OVERVIEW

Digestion of lipidsDigestion of lipids Triacylglycerol Triacylglycerol is the major is the major dietary lipid of nutritional valuedietary lipid of nutritional value

�� EmulsificationEmulsification–– Digestion of lipids begins in the duodenum, when the entrance of Digestion of lipids begins in the duodenum, when the entrance of

the the acid chyme acid chyme from the stomach stimulates secretion of from the stomach stimulates secretion of enteric hormones by the duodenal mucosa.enteric hormones by the duodenal mucosa.

–– Bile salts and phosphatidylcholine Bile salts and phosphatidylcholine act as detergents in the act as detergents in the duodenum due to their amphipathic structures. They aid in duodenum due to their amphipathic structures. They aid in formation of mixed micelles (which have a large surface area) formation of mixed micelles (which have a large surface area) duodenum due to their amphipathic structures. They aid in duodenum due to their amphipathic structures. They aid in formation of mixed micelles (which have a large surface area) formation of mixed micelles (which have a large surface area) from fat globules (which have a small surface area).from fat globules (which have a small surface area).

–– The micellar associations of lipids are the substrates for The micellar associations of lipids are the substrates for hydrolyzing enzymes.hydrolyzing enzymes.

�� Hydrolysis of triacylglycerols is effected by three Hydrolysis of triacylglycerols is effected by three enzymes.enzymes.–– Pancreatic lipase Pancreatic lipase cleaves triacylglycerols to 2cleaves triacylglycerols to 2--monoacylglycerol monoacylglycerol

and two fatty acids.and two fatty acids.–– Cholesterol esterase Cholesterol esterase hydrolyzes cholesterol esters to hydrolyzes cholesterol esters to

cholesterol plus a fatty acid. cholesterol plus a fatty acid. –– Phospholipase Phospholipase A2 hydrolyzes phospholipid.A2 hydrolyzes phospholipid.

CHYLOMICRON FORMATIONCHYLOMICRON FORMATIONFree fatty acids and monoacylglycerols are absorbed by Free fatty acids and monoacylglycerols are absorbed by intestinal epithelial cells. Triacylglycerols are intestinal epithelial cells. Triacylglycerols are resynthesized and packaged with other lipids and resynthesized and packaged with other lipids and apoprotein Bapoprotein B--48 to form chylomicrons, which are then 48 to form chylomicrons, which are then released into the lymph system.released into the lymph system.

Schematic Model of Low-Density Lipoprotein. The LDL particle is approximately 22 nm (220 Å) in diameter

Sites of lipoprotein formation and Sites of lipoprotein formation and transporttransport

�� The liver is the formation site of:The liver is the formation site of:–– Very lowVery low--density lipoproteinsdensity lipoproteins (VLDL),(VLDL), which transport triacylglycerols which transport triacylglycerols

from the liver to other tissues from the liver to other tissues –– HighHigh--density lipoproteinsdensity lipoproteins (HDL),(HDL), which transport excess cholesterol from which transport excess cholesterol from

other tissues to the liver and are sometimes referred to as "good" cholesterolother tissues to the liver and are sometimes referred to as "good" cholesterol�� The intestineThe intestine is the site of is the site of chylomicron formationchylomicron formation. . Chylomicrons are Chylomicrons are

triacylglycerols that are given a coat composed of protein, phospholipids, triacylglycerols that are given a coat composed of protein, phospholipids, and cholesterol esters.and cholesterol esters.–– Chylomicrons are transported in membraneChylomicrons are transported in membrane--bound vesicles to membranes of bound vesicles to membranes of –– Chylomicrons are transported in membraneChylomicrons are transported in membrane--bound vesicles to membranes of bound vesicles to membranes of

mucosal cells, where they are released by exocytosis into the extracellular mucosal cells, where they are released by exocytosis into the extracellular space. Once chylomicrons are in the plasma, most of the lipids contained in the space. Once chylomicrons are in the plasma, most of the lipids contained in the chylomicrons are removed by lipoprotein lipase, forming chylomicrons are removed by lipoprotein lipase, forming chylomicron chylomicron remnants,remnants,

–– Chylomicron remnants deliver dietary fat to the liver. The chylomicron Chylomicron remnants deliver dietary fat to the liver. The chylomicron remnants that remain after delipidation are enriched in cholesterol and remnants that remain after delipidation are enriched in cholesterol and cholesterol ester. They are cleared by the liver, where most of the cholesterol cholesterol ester. They are cleared by the liver, where most of the cholesterol is used for bile acid synthesis.is used for bile acid synthesis.

�� The plasmaThe plasma is the formation site of:is the formation site of:–– IntermediateIntermediate--density lipoproteinsdensity lipoproteins (IDL),(IDL), which are the initial product of which are the initial product of

VLDL degradationVLDL degradation–– LowLow--density lipoproteinsdensity lipoproteins (LDL),(LDL), which transport cholesterol esters which transport cholesterol esters –– Chylomicron remnantsChylomicron remnants

Properties of Major Plasma LipoproteinsProperties of Major Plasma Lipoproteins

HDL LDL IDL VLDL Chylomicron

Density (g/ml) 1.06-1.2 1.02-1.06 1.01-1.02 0.95-1.01 <0.95

Diameter (nm) 5-20 20-25 25-30 30-90 90-1 000

% Lipid 50-55 75-80 80-85 90-95 98

% Total lipid as:

Cholesterol (free) 3-4 7-10 8 5-10 1-3

Cholesterol ester 12 35-40 22 10-12 3-5

Phospholipid 20-25 15-20 22 15-20 7-9Phospholipid 20-25 15-20 22 15-20 7-9

Triacylglycerol 3 7-10 30 50-65 84-89

% Protein content 45-50 20-25 15-20 5-10 2

% Total protein as apoprotein (Apo):

ApoA-1,A-2,A-4 90-95 0 0 0-3 0-3

ApoB-48,B-100 0-2 95-100 50-60 40-50 20-22

ApoC-1,C-2,C-3 4-6 0-5 20 35-40 60-65

ApoD 0-2 0 0 0 1

ApoE 0-5 0 15-20 5-10 5

ReceptorReceptor--Mediated EndocytosisMediated Endocytosis

The process of receptorThe process of receptor--mediated endocytosis is illustrated mediated endocytosis is illustrated for the cholesterolfor the cholesterol--carrying complex, lowcarrying complex, low--density density lipoprotein (LDL): lipoprotein (LDL):

�� (1) LDL binds to a specific receptor, the LDL receptor;(1) LDL binds to a specific receptor, the LDL receptor;

�� (2) this complex invaginates to form an internal vesicle; (2) this complex invaginates to form an internal vesicle;

�� (3) after separation from its receptor, the LDL(3) after separation from its receptor, the LDL--containing containing vesicle fuses with a lysosome, leading to degradation of vesicle fuses with a lysosome, leading to degradation of the LDL and release of the cholesterolthe LDL and release of the cholesterol

Endocytosis of LDL Bound to Its ReceptorEndocytosis of LDL Bound to Its Receptor

�� (A) Electron micrograph showing LDL (A) Electron micrograph showing LDL (conjugated to ferritin for visualization, dark (conjugated to ferritin for visualization, dark spots) bound to a coatedspots) bound to a coated--pit region on the pit region on the surface of a cultured human fibroblast cell.surface of a cultured human fibroblast cell.

�� (B) Micrograph showing this region (B) Micrograph showing this region invaginating and fusing to form an endocytic invaginating and fusing to form an endocytic vesiclevesicle

Disorders of lipoprotein Disorders of lipoprotein metabolismmetabolism

�� HyperlipidemiasHyperlipidemias represent an represent an abnormally high level of plasma abnormally high level of plasma lipoproteins. lipoproteins. lipoproteins. lipoproteins.

�� The most serious consequence of The most serious consequence of hyperlipidemias is increased risk of hyperlipidemias is increased risk of atherosclerosis,atherosclerosis, an arterial disease an arterial disease that causes heart attacks and stroke.that causes heart attacks and stroke.

Types of HyperlipidemiasTypes of Hyperlipidemias

Type Generic Classification Increased

Lipoprotein

Increased Lipid

I Lipoprotein lipase deficiency Chylomicrons Triacylglycerols

IIa Hypercholesterolemia

(LDL receptor deficiency)

LDL Cholesterol

(LDL receptor deficiency)

IIb Combined hyperlipidemia LDL, VLDL Triacylglycerols,

cholesterol

III Dysbetalipoproteinemia β-VLDL Triacylglycerols,

cholesterol

IV Hypertriglyceridemia VLDL Triacylglycerols

V Mixed hyperlipidemia VLDL,

chylomicrons

Triacylglycerols

AN ATHEROSCLEROTIC PLAQUEAN ATHEROSCLEROTIC PLAQUE

�� A plaque (marked by A plaque (marked by an arrow) blocks most an arrow) blocks most an arrow) blocks most an arrow) blocks most of the lumen of this of the lumen of this blood vessel. The blood vessel. The plaque is rich in plaque is rich in cholesterol.cholesterol.

HypolipidemiasHypolipidemias are caused by a deficiency of one are caused by a deficiency of one or more of the plasma lipoproteinsor more of the plasma lipoproteins

�� HypobetalipoproteinemiaHypobetalipoproteinemia (abetalipoproteinemia) is (abetalipoproteinemia) is a genetic disorder characterized by neurologic a genetic disorder characterized by neurologic symptoms, including ataxia and mental retardation. symptoms, including ataxia and mental retardation. –– Plasma triacylglycerol and cholesterol levels are decreased.Plasma triacylglycerol and cholesterol levels are decreased.–– There is a complete absence of (3There is a complete absence of (3--lipoproteins (no lipoproteins (no –– There is a complete absence of (3There is a complete absence of (3--lipoproteins (no lipoproteins (no

chylomicrons or VLDLs).chylomicrons or VLDLs).–– Absorption of fat is greatly reduced.Absorption of fat is greatly reduced.

�� HDL deficiency (Tangier disease)HDL deficiency (Tangier disease) is characterized is characterized by recurrent polyneuropathy, lymphadenopathy, by recurrent polyneuropathy, lymphadenopathy, tonsillar hyperplasia, and hepatosplenomegaly (from tonsillar hyperplasia, and hepatosplenomegaly (from storage of cholesterol in reticuloendothelial cells).storage of cholesterol in reticuloendothelial cells).–– Plasma cholesterol levels are low; triacylglycerols are normal Plasma cholesterol levels are low; triacylglycerols are normal

or increasedor increased–– There is a marked decrease in plasma HDLsThere is a marked decrease in plasma HDLs

FATTY ACIDS BIOSYNTHESISFATTY ACIDS BIOSYNTHESIS

GENERAL FEATURES OF FATTY ACIDS GENERAL FEATURES OF FATTY ACIDS BIOSYNTHESISBIOSYNTHESIS�� Fatty acids may be synthesized from dietary glucose via Fatty acids may be synthesized from dietary glucose via pyruvate.pyruvate.

�� Fatty acids are the preferred fuel source for the heart and Fatty acids are the preferred fuel source for the heart and the primary form in which excess fuel is stored in adipose the primary form in which excess fuel is stored in adipose tissue.tissue.

�� The major site of fatty acid synthesis is the The major site of fatty acid synthesis is the liver.liver.�� The enzymes that synthesize fatty acids are localized in The enzymes that synthesize fatty acids are localized in �� The enzymes that synthesize fatty acids are localized in The enzymes that synthesize fatty acids are localized in the the cytosol,cytosol, and they are completely different from the and they are completely different from the mitochondrial enzymes that catalyze fatty acid mitochondrial enzymes that catalyze fatty acid degradation.degradation.

�� The major synthetic pathway involves polymerization of The major synthetic pathway involves polymerization of twotwo--carbon units derived from carbon units derived from acetyl coenzyme Aacetyl coenzyme A(acetyl CoA)(acetyl CoA) to form a sixteento form a sixteen--carbon saturated fatty carbon saturated fatty acid, palmitic acid.acid, palmitic acid.

�� Reduced nicotinamide adenine dinucleotide phosphate Reduced nicotinamide adenine dinucleotide phosphate (NADPH) and adenosine triphosphate (ATP) are required (NADPH) and adenosine triphosphate (ATP) are required for fatty acid synthesis.for fatty acid synthesis.

Sources of acetyl CoA and NADPHSources of acetyl CoA and NADPH�� CytosolCytosol

–– Acetyl CoA is derived from the oxidation of Acetyl CoA is derived from the oxidation of glucose via glycolysis and pyruvate glucose via glycolysis and pyruvate dehydrogenase. dehydrogenase.

–– NADPH is generated by the pentose NADPH is generated by the pentose phosphate pathway.phosphate pathway.phosphate pathway.phosphate pathway.

Sources of acetyl CoA and NADPHSources of acetyl CoA and NADPH�� Mitochondria: The acetyl CoA shuttle systemMitochondria: The acetyl CoA shuttle system. . Acetyl CoA cannot cross the inner mitochondrial Acetyl CoA cannot cross the inner mitochondrial membrane and is transported to the cytosol via this membrane and is transported to the cytosol via this shuttle, which also produces NADPH in the cytosol. shuttle, which also produces NADPH in the cytosol. –– Citrate synthetase catalyzes the reaction of acetyl CoA with Citrate synthetase catalyzes the reaction of acetyl CoA with oxaloacetate to form citrate in the mitochondria.oxaloacetate to form citrate in the mitochondria.

–– Citrate is transported into the cytosol by a tricarboxylic acid Citrate is transported into the cytosol by a tricarboxylic acid transport system. transport system.

–– Citrate reacts with CoA in the cytosol to form acetyl CoA and Citrate reacts with CoA in the cytosol to form acetyl CoA and –– Citrate reacts with CoA in the cytosol to form acetyl CoA and Citrate reacts with CoA in the cytosol to form acetyl CoA and oxaloacetate (OAA). oxaloacetate (OAA).

–– OAA is converted to malate by an oxidized nicotinamide adenine OAA is converted to malate by an oxidized nicotinamide adenine dinucleotide (NADdinucleotide (NAD++))--dependent cytosolic malate dehydrogenase.dependent cytosolic malate dehydrogenase.

–– Malate is decarboxylated to form pyruvate by the malic enzyme, Malate is decarboxylated to form pyruvate by the malic enzyme, which also forms NADPH from oxidized nicotinamide adenine which also forms NADPH from oxidized nicotinamide adenine dinucleotide phosphate (NADPdinucleotide phosphate (NADP++).).

–– Pyruvate is transported into the mitochondria by an active Pyruvate is transported into the mitochondria by an active transport system.transport system.

–– OAA is regenerated from pyruvate by pyruvate carboxylase.OAA is regenerated from pyruvate by pyruvate carboxylase.

Acetyl CoA carboxylaseAcetyl CoA carboxylase

�� This enzyme catalyzes the ATPThis enzyme catalyzes the ATP--dependent carboxylation of dependent carboxylation of acetyl CoA to malonyl CoA. acetyl CoA to malonyl CoA.

�� This is the This is the key regulatory sitekey regulatory site for fatty acid synthesis.for fatty acid synthesis.–– ActivatorsActivators are citrate and insulin.are citrate and insulin.–– InhibitorsInhibitors are palmitoyl CoA and glucagon.are palmitoyl CoA and glucagon.

�� BiotinBiotin is a required cofactor. Acetyl CoA carboxylase is one of is a required cofactor. Acetyl CoA carboxylase is one of the enzymes that is inactive in the condition known as the enzymes that is inactive in the condition known as multiple carboxylasemultiple carboxylase deficiencydeficiency, which is due to an , which is due to an inability to utilize biotin.inability to utilize biotin.

Animal Fatty Acid SynthaseAnimal Fatty Acid Synthase

Schematic Representation of Animal Fatty Acid SynthaseSchematic Representation of Animal Fatty Acid Synthase

�� Each of the identical chains in the dimer contains three domains. Each of the identical chains in the dimer contains three domains. �� Domain 1 (blue) contains acetyl transferase (AT), malonyl transferase (MT), and condensing Domain 1 (blue) contains acetyl transferase (AT), malonyl transferase (MT), and condensing

enzyme (CE). enzyme (CE). �� Domain 2 (yellow) contains acyl carrier protein (ACP), βDomain 2 (yellow) contains acyl carrier protein (ACP), β--ketoacyl reductase (KR), dehydratase ketoacyl reductase (KR), dehydratase

(DH), and enoyl reductase (ER). Domain 3 (red) contains thioesterase (TE). (DH), and enoyl reductase (ER). Domain 3 (red) contains thioesterase (TE). �� The flexible phosphopantetheinyl group (green) carries the fatty acyl chain from one catalytic The flexible phosphopantetheinyl group (green) carries the fatty acyl chain from one catalytic

site on a chain to another, as well as between chains in the dimersite on a chain to another, as well as between chains in the dimer

The fatty acid synthase enzyme complexThe fatty acid synthase enzyme complexcatalyzes several reactions that convert catalyzes several reactions that convert acetyl CoA and malonyl CoA to butyryl CoAacetyl CoA and malonyl CoA to butyryl CoA

�� The acetyl transacylaseThe acetyl transacylase component catalyzes the component catalyzes the conversion ofconversion of

acetyl CoA + acyl carrier protein (ACP) acetyl CoA + acyl carrier protein (ACP) →→ acetylacetyl--ACP + CoAACP + CoA

–– ACP possesses a ACP possesses a phosphopantetheine prosthetic group, phosphopantetheine prosthetic group, which is derived from the vitamin pantothenic acid and is which is derived from the vitamin pantothenic acid and is which is derived from the vitamin pantothenic acid and is which is derived from the vitamin pantothenic acid and is identical to that portion of the CoA molecule.identical to that portion of the CoA molecule.

–– The acyl groups of the substrate molecules are covalently The acyl groups of the substrate molecules are covalently bound to ACP via a thioester linkage with the terminal bound to ACP via a thioester linkage with the terminal sulfhydryl group.sulfhydryl group.

�� The malonyl transacylaseThe malonyl transacylase component catalyzes component catalyzes the conversion of the conversion of malonyl CoA + ACP malonyl CoA + ACP →→ malonylmalonyl--ACP + CoAACP + CoA

PhosphopantetheinePhosphopantetheine

�� Both acyl carrier protein and CoA include Both acyl carrier protein and CoA include phosphopantetheine as their reactive units. ACP, a phosphopantetheine as their reactive units. ACP, a single polypeptide chain of 77 residues, can be single polypeptide chain of 77 residues, can be regarded as a giant prosthetic group, a “macro CoA.”regarded as a giant prosthetic group, a “macro CoA.”

�� The 3The 3--ketoacyl synthaseketoacyl synthase component catalyzes component catalyzes the conversion of the conversion of

malonylmalonyl--ACP + acetylACP + acetyl--ACP ACP →→ acetoacetylacetoacetyl--ACP + ACP + COACP + ACP + CO22

�� The 3The 3--ketoacyl reductaseketoacyl reductase component component catalyzes the NADPHcatalyzes the NADPH--dependent conversion of dependent conversion of catalyzes the NADPHcatalyzes the NADPH--dependent conversion of dependent conversion of acetoacetylacetoacetyl--ACP ACP →→ 33--hydroxybutyrylhydroxybutyryl--ACPACP

�� The 3The 3--hydroxybutyrylhydroxybutyryl--ACP dehydrataseACP dehydratasecomponent catalyzes the conversion of component catalyzes the conversion of 33--hydroxybutyrylhydroxybutyryl--ACP ACP →→ crotonylcrotonyl--ACPACP..

�� The enoylThe enoyl--ACP reductaseACP reductase component catalyzes component catalyzes the NADPHthe NADPH--dependent conversion of dependent conversion of

crotonylcrotonyl--ACP ACP →→ butyrylbutyryl--ACPACP

Formation of palmitic acidFormation of palmitic acid�� Reaction.Reaction. ButyrylButyryl--ACP (a fourACP (a four--carbon unit) reacts with carbon unit) reacts with another malonyl group via the reactions described above another malonyl group via the reactions described above to form a sixto form a six--carbon unit, and the reactions of the fatty carbon unit, and the reactions of the fatty acid synthase complex continue. acid synthase complex continue.

�� Reaction repeats.Reaction repeats. After After seven turns seven turns of this cycle, of this cycle, palmiticpalmitic--ACP (a 16ACP (a 16--carbon unit) is synthesized. carbon unit) is synthesized.

�� Release.Release. Palmitic acid is released from ACP and the Palmitic acid is released from ACP and the �� Release.Release. Palmitic acid is released from ACP and the Palmitic acid is released from ACP and the fatty acid synthase complex fatty acid synthase complex by palmitoyl deacylaseby palmitoyl deacylase(thioesterase).(thioesterase).

Stoichiometry of the synthesis of Stoichiometry of the synthesis of palmitatepalmitate

8 Acetyl CoA + 7 ATP + 14 NADPH + 14 H8 Acetyl CoA + 7 ATP + 14 NADPH + 14 H++ + H+ H22O O →→

→→ Palmitate + 7 ADP + 7PPalmitate + 7 ADP + 7Pii + 8 CoASH + 14 NADP+ 8 CoASH + 14 NADP++

Elongation of fatty acidsElongation of fatty acids. .

�� Fatty acids longer than 16 carbons can be formed Fatty acids longer than 16 carbons can be formed via one of two elongation systems adding 2via one of two elongation systems adding 2--carbon carbon unitsunits

�� The endoplasmic reticulum systemThe endoplasmic reticulum system is the most active. is the most active. �� The endoplasmic reticulum systemThe endoplasmic reticulum system is the most active. is the most active. It adds malonyl CoA onto palmitate in a manner similar to It adds malonyl CoA onto palmitate in a manner similar to the action of fatty acid synthase, except that CoASH is the action of fatty acid synthase, except that CoASH is used rather than the ACP. Stearic acid (an 18used rather than the ACP. Stearic acid (an 18--carbon unit) carbon unit) is the product.is the product.

�� A mitochondrial elongation system A mitochondrial elongation system uses acetyl CoA uses acetyl CoA units, rather than malonyl CoA units, to elongate fatty units, rather than malonyl CoA units, to elongate fatty acids for the synthesis of structural lipids in this organelle.acids for the synthesis of structural lipids in this organelle.

Desaturation of fatty acidsDesaturation of fatty acids

�� The two most common monounsaturated fatty The two most common monounsaturated fatty acids in mammals are palmitoleic acid (16:1:acids in mammals are palmitoleic acid (16:1:∆∆99) ) and oleic acid (18:1:and oleic acid (18:1:∆∆99).).

�� In the endoplasmic reticulum, double bonds are In the endoplasmic reticulum, double bonds are �� In the endoplasmic reticulum, double bonds are In the endoplasmic reticulum, double bonds are introduced between carbons 9 and 10 by introduced between carbons 9 and 10 by fatty fatty acid oxygenaseacid oxygenase, , which requires molecular oxygen which requires molecular oxygen (O(O22) and NADPH) and NADPH

FATTY ACID OXIDATIONFATTY ACID OXIDATION

�� Fatty acids are an important energy Fatty acids are an important energy source. source.

�� Oxidation of fatty acids generates the Oxidation of fatty acids generates the �� Oxidation of fatty acids generates the Oxidation of fatty acids generates the highhigh--energy compounds reduced NAD energy compounds reduced NAD (NADH) and reduced flavin adenine (NADH) and reduced flavin adenine dinucleotide (FADHdinucleotide (FADH22) and yields acetyl ) and yields acetyl CoA, which is the substrate for the citric CoA, which is the substrate for the citric acid cycleacid cycle

ββββββββ--Oxidation of fatty acidsOxidation of fatty acids

�� ββ--Oxidation of fatty acids is the Oxidation of fatty acids is the principal pathway. principal pathway.

�� It occurs in the mitochondrial matrix It occurs in the mitochondrial matrix �� It occurs in the mitochondrial matrix It occurs in the mitochondrial matrix and involves oxidation of the and involves oxidation of the ββ--carbon carbon to form a to form a ββ--keto acidketo acid

Activation of free fatty acidsActivation of free fatty acids

�� Free fatty acids are taken up from the circulation Free fatty acids are taken up from the circulation by cells and are activated by formation of acyl CoA by cells and are activated by formation of acyl CoA derivatives. derivatives. –– An endoplasmic reticulum acyl CoA synthetaseAn endoplasmic reticulum acyl CoA synthetase–– An endoplasmic reticulum acyl CoA synthetaseAn endoplasmic reticulum acyl CoA synthetase

(thiokinase) activates long(thiokinase) activates long--chain fatty acids of 12 or chain fatty acids of 12 or more carbons.more carbons.

Fatty acid + ATP + CoASH Fatty acid + ATP + CoASH →→ acylCoA + PPacylCoA + PPii + AMP+ AMP–– Inner mitochondrial acyl CoA synthetasesInner mitochondrial acyl CoA synthetases activate activate

mediummedium--chain (4chain (4--10 carbons) and short10 carbons) and short--chain (acetate chain (acetate and propionate) fatty acids. These fatty acids enter the and propionate) fatty acids. These fatty acids enter the mitochondria freely from the cytoplasm, whereas the mitochondria freely from the cytoplasm, whereas the longlong--chain fatty acids cannot.chain fatty acids cannot.

Role of carnitineRole of carnitine

�� LongLong--chain fatty acyl CoAs cannot chain fatty acyl CoAs cannot freely diffuse across the inner freely diffuse across the inner mitochondrial membrane. mitochondrial membrane. mitochondrial membrane. mitochondrial membrane.

�� Carnitine in the inner mitochondrial Carnitine in the inner mitochondrial membrane mediates transfer of fatty membrane mediates transfer of fatty acyl groups from the cytosol to the acyl groups from the cytosol to the mitochondrial matrix where they are mitochondrial matrix where they are oxidized. oxidized.

Transfer reactionTransfer reaction

�� Sources of carnitineSources of carnitine�� Sources of carnitineSources of carnitine–– DietaryDietary sources include red meat and dairy products.sources include red meat and dairy products.–– Synthesis.Synthesis. Carnitine (Carnitine (ββ--hydroxyhydroxy--γγ--trimethylammonium trimethylammonium

butyrate) may be synthesized in the body from the amino butyrate) may be synthesized in the body from the amino acid lysine. acid lysine.

�� Carnitine deficiencyCarnitine deficiency in humans may be classified in humans may be classified as:as:–– Systemic,Systemic, in which levels are reduced in all tissuesin which levels are reduced in all tissues–– Myopathic,Myopathic, in which levels are reduced only in muscle, in which levels are reduced only in muscle,

including the heartincluding the heart

Transfer reactionTransfer reaction

On the outer surface of the On the outer surface of the inner mitochondrial inner mitochondrial membrane, the enzyme membrane, the enzyme carnitine palmitoyl carnitine palmitoyl transferase I (CPT transferase I (CPT I)I)catalyzes the transfer of catalyzes the transfer of the acyl group from CoA to the acyl group from CoA to carnitine. The fatty acyl carnitine. The fatty acyl

CPT - carnitine palmitoyl transferase

carnitine. The fatty acyl carnitine. The fatty acyl group is translocated group is translocated across the membrane to across the membrane to the inner surface, where the inner surface, where the enzyme the enzyme carnitine carnitine palmitoyl transferase II palmitoyl transferase II (CPT II)(CPT II) catalyzes the catalyzes the transfer of the acyl group transfer of the acyl group to CoA drawn from the to CoA drawn from the matrix CoA poolmatrix CoA pool

�� Reaction Sequence for the Reaction Sequence for the Degradation of Fatty Acids. Degradation of Fatty Acids. Fatty acids are degraded by Fatty acids are degraded by Fatty acids are degraded by Fatty acids are degraded by the repetition of a fourthe repetition of a four--reaction sequence consisting reaction sequence consisting of oxidation, hydration, of oxidation, hydration, oxidation, and thiolysisoxidation, and thiolysis

Pathway of Pathway of ββββββββ--oxidationoxidation

�� In the mitochondrial matrix, longIn the mitochondrial matrix, long--chain fatty acyl CoAs are subjected to chain fatty acyl CoAs are subjected to a a repeated fourrepeated four--step processstep process that successively removes twothat successively removes two--carbon carbon units from the chain until the last twounits from the chain until the last two--carbon fragment remains.carbon fragment remains.

Acyl CoA Acyl CoA →→ enoyl CoAenoyl CoA–– This This dehydrogenationdehydrogenation reaction is catalyzed by a family of reaction is catalyzed by a family of acyl CoA dehyacyl CoA dehy--drogenasesdrogenases with varying specificity for different length acyl CoA chains.with varying specificity for different length acyl CoA chains.

–– The prosthetic group of this enzyme, flavin adenine dinucleotide (FAD), is The prosthetic group of this enzyme, flavin adenine dinucleotide (FAD), is reduced to FADHreduced to FADH22 during this reaction.during this reaction.

–– Genetic defectsGenetic defects in acyl CoA dehydrogenases (e.g., mediumin acyl CoA dehydrogenases (e.g., medium--chain acyl CoA chain acyl CoA –– Genetic defectsGenetic defects in acyl CoA dehydrogenases (e.g., mediumin acyl CoA dehydrogenases (e.g., medium--chain acyl CoA chain acyl CoA dehydrogenase deficiency) impair dehydrogenase deficiency) impair ββ--oxidation. oxidation.

Enoyl CoA Enoyl CoA →→ 33--hydroxyacyl CoAhydroxyacyl CoA–– This This hydrationhydration reaction is catalyzed by reaction is catalyzed by enoyl CoA hydrataseenoyl CoA hydratase. .

33--Hydroxyacyl CoA Hydroxyacyl CoA →→ 33--ketoacyl CoAketoacyl CoA–– This This dehydrogenationdehydrogenation reaction is catalyzed by 3reaction is catalyzed by 3--hydroxyacyl hydroxyacyl CoA CoA

dehydrogenasedehydrogenase..–– NAD+ is reduced to NADH during this reaction.NAD+ is reduced to NADH during this reaction.33--Ketoacyl CoA + CoASH Ketoacyl CoA + CoASH →→ acetyl CoA + tetradecanoyl CoAacetyl CoA + tetradecanoyl CoA–– This This thiolytic cleavagethiolytic cleavage reaction is catalyzed by reaction is catalyzed by thiolasethiolase ((ββ--ketothiolase)ketothiolase)

First Three Rounds in the Degradation of Palmitate. Two-carbon units are Two-carbon units are sequentially removed from the carboxyl end of the fatty acid

Stoichiometry of Stoichiometry of ββββββββ--oxidationoxidation

�� ββββββββ--Oxidation of palmitate (16 carbons)Oxidation of palmitate (16 carbons)

PalmitoylCoA + 7CoASH + 7FAD + 7NADPalmitoylCoA + 7CoASH + 7FAD + 7NAD++ + 7 H+ 7 H22O O →→→→ 8 acetylCoA + 7FADH8 acetylCoA + 7FADH22 + 7NADH + 7H+ 7NADH + 7H++ ((11))–– total of 7 moles of FADH2 yields 14 moles of ATP by electron total of 7 moles of FADH2 yields 14 moles of ATP by electron transport and oxidative phosphorylation. A total of 7 moles transport and oxidative phosphorylation. A total of 7 moles of NADH yields 21 moles of ATP by electron transport and of NADH yields 21 moles of ATP by electron transport and of NADH yields 21 moles of ATP by electron transport and of NADH yields 21 moles of ATP by electron transport and oxidative phosphorylation. Therefore,oxidative phosphorylation. Therefore,

PalmitoylCoA + 7CoASH + 7OPalmitoylCoA + 7CoASH + 7O22 + 35ADP + 35P+ 35ADP + 35Pii →→

→→ 8 acetylCoA + 35ATP + 42H8 acetylCoA + 35ATP + 42H22OO ((22))�� Because it costs 2 moles of ATP to activate the free Because it costs 2 moles of ATP to activate the free palmitate, palmitate, 33 moles of ATP are formed per mole 33 moles of ATP are formed per mole of palmitate via of palmitate via ββββββββ--oxidationoxidation..

Total oxidationTotal oxidation

�� The acetyl CoA derived from The acetyl CoA derived from ββ--oxidation of fatty acyl CoAs may oxidation of fatty acyl CoAs may be oxidized to carbon dioxide (CObe oxidized to carbon dioxide (CO22) and water (H) and water (H22O) by the O) by the citric acid cycle.citric acid cycle.

8 Acetyl CoA + 16 O8 Acetyl CoA + 16 O22 + 96 ADP + 96 P+ 96 ADP + 96 Pii →→

→→ 8 CoASH + 96 ATP + 16 CO8 CoASH + 96 ATP + 16 CO22 + 104 H+ 104 H22OO (3)(3)→→ 8 CoASH + 96 ATP + 16 CO8 CoASH + 96 ATP + 16 CO22 + 104 H+ 104 H22OO (3)(3)�� The combined yield of ATP is obtained by addition of equations The combined yield of ATP is obtained by addition of equations (2) and (3)(2) and (3)

Palmitoyl CoA + 23 OPalmitoyl CoA + 23 O22 + 131 ADP + 131 P+ 131 ADP + 131 Pii →→

→→ 8 CoASH + 131 ATP + 16 CO8 CoASH + 131 ATP + 16 CO22 + 146 H+ 146 H22OO ((44))�� After subtraction of 2 moles of ATP for activation of the fatty After subtraction of 2 moles of ATP for activation of the fatty acyl CoA, acyl CoA, 129 moles of ATP are formed by total oxidation 129 moles of ATP are formed by total oxidation of palmitateof palmitate..

Respiratory quotient (RQ)Respiratory quotient (RQ)

�� Respiratory quotient (RQ)Respiratory quotient (RQ) is defined is defined as moles of COas moles of CO22 produced, divided by produced, divided by moles of oxygen consumed during moles of oxygen consumed during complete oxidation of a metabolic fuel to complete oxidation of a metabolic fuel to complete oxidation of a metabolic fuel to complete oxidation of a metabolic fuel to COCO22 and Hand H22O. O. –– For palmitate, the RQ is given by:For palmitate, the RQ is given by:(16 moles CO(16 moles CO22 produced)/(23 moles Oproduced)/(23 moles O22

consumed) = consumed) = 0.70.7–– In contrast, the complete oxidation of In contrast, the complete oxidation of glucose yields an RQ of glucose yields an RQ of 1.01.0

Oxidation of fatty acids with an Oxidation of fatty acids with an odd number of carbon atomsodd number of carbon atoms

�� Fatty acids that have an odd number of Fatty acids that have an odd number of carbon atoms are a minor species in human carbon atoms are a minor species in human tissues.tissues.

They undergo They undergo ββ--oxidation as acyl CoA derivatives until oxidation as acyl CoA derivatives until �� They undergo They undergo ββ--oxidation as acyl CoA derivatives until oxidation as acyl CoA derivatives until a threea three--carbon fragment, propionyl CoA, is formed.carbon fragment, propionyl CoA, is formed.

�� Propionyl CoA is carboxylated to methylmalonyl CoA by Propionyl CoA is carboxylated to methylmalonyl CoA by biotinbiotin--dependent dependent propionyl CoA carboxylasepropionyl CoA carboxylase..

�� Methylmalonyl CoA is converted to succinyl CoA by Methylmalonyl CoA is converted to succinyl CoA by methylmalonyl CoA mutasemethylmalonyl CoA mutase..

�� Succinyl CoA can be metabolized via the citric acid Succinyl CoA can be metabolized via the citric acid cycle, of which it is an intermediate.cycle, of which it is an intermediate.

Conversion of Propionyl CoA Conversion of Propionyl CoA Into Succinyl CoAInto Succinyl CoA

�� Propionyl CoA, generated from fatty acids Propionyl CoA, generated from fatty acids with an odd number of carbons as well as with an odd number of carbons as well as some amino acids, is converted into the some amino acids, is converted into the citric acid cycle intermediate succinyl CoA.citric acid cycle intermediate succinyl CoA.

Oxidation of unsaturated Oxidation of unsaturated fatty acidsfatty acids

�� In the human body, 50% of the fatty acids are In the human body, 50% of the fatty acids are unsaturated. Many unsaturated fatty acids are unsaturated. Many unsaturated fatty acids are degraded by the degraded by the ββ--oxidation pathway with the help oxidation pathway with the help of two additional enzymes.of two additional enzymes.Double bonds in naturally occurring fatty acids are Double bonds in naturally occurring fatty acids are �� Double bonds in naturally occurring fatty acids are Double bonds in naturally occurring fatty acids are cis. cis. The The ββ--oxidation pathway can only process oxidation pathway can only process trans trans double bonds using enoyl CoA hydratase.double bonds using enoyl CoA hydratase.

�� The The cis cis double bond is removed by the sequential double bond is removed by the sequential reactions catalyzed by 2,4reactions catalyzed by 2,4--dienoyl CoA reductase dienoyl CoA reductase and enoyl CoA isomerase to yield a and enoyl CoA isomerase to yield a ∆∆22--trans enoyl trans enoyl CoA.CoA.

Oxidation of unsaturated fatty acidsOxidation of unsaturated fatty acids

�� In the human body, 50% of the fatty acids are unsaturated. Many In the human body, 50% of the fatty acids are unsaturated. Many unsaturated fatty acids are degraded by the unsaturated fatty acids are degraded by the ββ--oxidation pathway oxidation pathway with the help of two additional enzymes.with the help of two additional enzymes.–– Double bonds in naturally occurring fatty acids are Double bonds in naturally occurring fatty acids are cis. cis. The The ββ--oxidation oxidation

pathway can only process pathway can only process trans trans double bonds using enoyl CoA double bonds using enoyl CoA hydratase.hydratase.

–– The The cis cis double bond is removed by the sequential reactions catalyzed by double bond is removed by the sequential reactions catalyzed by 2,42,4--dienoyl CoA reductase and enoyl CoA isomerase to yield a dienoyl CoA reductase and enoyl CoA isomerase to yield a ∆∆22--trans trans enoyl CoA.enoyl CoA.

αααααααα--Oxidation of fatty acidsOxidation of fatty acids

�� This This pathwaypathway involves the oxidation of longinvolves the oxidation of long--chain fatty chain fatty acids to 2acids to 2--hydroxy fatty acids, which are constituents of hydroxy fatty acids, which are constituents of brain lipids, followed by oxidation to a fatty acid with one brain lipids, followed by oxidation to a fatty acid with one less carbon. Removal of one carbon from the carboxyl end less carbon. Removal of one carbon from the carboxyl end less carbon. Removal of one carbon from the carboxyl end less carbon. Removal of one carbon from the carboxyl end of a fatty acid has been demonstrated in microsomal of a fatty acid has been demonstrated in microsomal fractions from fractions from brain brain tissue.tissue.

�� Refsum's diseaseRefsum's disease (phytanic acid storage disease) is (phytanic acid storage disease) is caused by a defect of caused by a defect of αα--oxidation.oxidation.–– Phytanic acidPhytanic acid (derived from animal fat and cow's milk and (derived from animal fat and cow's milk and probably originally from chlorophyll) accumulates in affected probably originally from chlorophyll) accumulates in affected individuals. Phytanic acid cannot alternatively be oxidized by individuals. Phytanic acid cannot alternatively be oxidized by ββ--oxidation because the beta position is blocked by a methyl group.oxidation because the beta position is blocked by a methyl group.

�� SymptomsSymptoms include retinitis pigmentosa, failing night include retinitis pigmentosa, failing night vision, peripheral neuropathy, and cerebellar ataxia.vision, peripheral neuropathy, and cerebellar ataxia.

ωωωωωωωω--OxidationOxidation

�� ωωωωωωωω--OxidationOxidation involves oxidation of the involves oxidation of the terminal methyl group to form an terminal methyl group to form an ωωωωωωωω--hydroxy fatty acid. hydroxy fatty acid. hydroxy fatty acid. hydroxy fatty acid.

�� This is a minor pathway observed with This is a minor pathway observed with liver microsomal preparationsliver microsomal preparations

BIOSYNTHESIS OF TRIACYLGLYCEROLS BIOSYNTHESIS OF TRIACYLGLYCEROLS (TRIGLYCERIDES)(TRIGLYCERIDES)

�� Fatty acids are converted to Fatty acids are converted to triacylglycerols for transport to tissues triacylglycerols for transport to tissues triacylglycerols for transport to tissues triacylglycerols for transport to tissues and storage.and storage.

�� FormationFormation involves the acylation of involves the acylation of the three hydroxyl groups of glycerolthe three hydroxyl groups of glycerol

Activation of the fatty acidActivation of the fatty acid

�� 1. 1. Formation of the CoA ester of the Formation of the CoA ester of the fatty acid is catalyzed in the fatty acid is catalyzed in the cytosolcytosolby an ATPby an ATP--dependent dependent acyl CoA acyl CoA by an ATPby an ATP--dependent dependent acyl CoA acyl CoA synthetasesynthetase..

Fatty acid + ATP + CoASH Fatty acid + ATP + CoASH →→ Acyl CoA Acyl CoA + AMP + PP+ AMP + PPii

Acylation of glycerolAcylation of glycerol

�� First acylation.First acylation. There are two routes for the acylation of the There are two routes for the acylation of the first hydroxyl of glycerol.first hydroxyl of glycerol.

�� One route uses One route uses dihydroxyacetone phosphate (DHAPdihydroxyacetone phosphate (DHAP), ), derived from derived from glycolysis, as the acceptor of an acyl moiety from a fatty acyl CoA.glycolysis, as the acceptor of an acyl moiety from a fatty acyl CoA.–– This is followed by reduction, with This is followed by reduction, with NADPH NADPH as the electron acceptor, to form as the electron acceptor, to form lysophosphatidate.lysophosphatidate.

–– The fatty acid preferentially introduced to form lysophosphatidate is saturated.The fatty acid preferentially introduced to form lysophosphatidate is saturated.�� The second route gives the same product and shows the same preference The second route gives the same product and shows the same preference �� The second route gives the same product and shows the same preference The second route gives the same product and shows the same preference

for a saturated fatty acid, but the order is reversed, and reduction of DHAP for a saturated fatty acid, but the order is reversed, and reduction of DHAP to glycerolto glycerol--33--phosphate occurs before acylation of the Cphosphate occurs before acylation of the C--1 hydroxyl. 1 hydroxyl.

�� Second acylationSecond acylation. . An unsaturated fatty acyl CoA thioester An unsaturated fatty acyl CoA thioester is introduced to the 2is introduced to the 2--hydroxyl of lysophosphatidate. An hydroxyl of lysophosphatidate. An exception occurs in the human mammary gland, where a exception occurs in the human mammary gland, where a saturated fatty acyl CoA is used.saturated fatty acyl CoA is used.

�� Third acylationThird acylation. . The phosphate group on CThe phosphate group on C--3 is removed by 3 is removed by a phosphatase and either a saturated or unsaturated fatty a phosphatase and either a saturated or unsaturated fatty acid is incorporated at that position.acid is incorporated at that position.

Storage of triacylglycerols in Storage of triacylglycerols in

adipose tissue cellsadipose tissue cells (adipocytes)(adipocytes)

�� The esterification of fatty acids in adipocytes to The esterification of fatty acids in adipocytes to form triacylglycerols depends on carbohydrate form triacylglycerols depends on carbohydrate metabolism for the formation of DHAP.metabolism for the formation of DHAP.

�� Adipocytes lack a glycerol kinase and cannot Adipocytes lack a glycerol kinase and cannot phosphorylate glycerol to glycerolphosphorylate glycerol to glycerol--33--phosphate. The phosphate. The phosphorylate glycerol to glycerolphosphorylate glycerol to glycerol--33--phosphate. The phosphate. The only source of glycerolonly source of glycerol--33--phosphate for phosphate for triacylglycerol synthesis is from DHAP formed triacylglycerol synthesis is from DHAP formed during glycolysis.during glycolysis.

�� The entry of glucose into adipocytes is insulin The entry of glucose into adipocytes is insulin dependent. Thus, insulin is an essential dependent. Thus, insulin is an essential requirement for triacylglycerol synthesis in requirement for triacylglycerol synthesis in adipocytes.adipocytes.

Lipolysis of triacylglycerolsLipolysis of triacylglycerols�� Hormonal control of lipolysis in adipocytesHormonal control of lipolysis in adipocytes

–– HormoneHormone--sensitive lipasesensitive lipase is activated by covalent is activated by covalent phosphorylation of the lipase by a cyclic adenosine phosphorylation of the lipase by a cyclic adenosine monophosphate (cAMP)monophosphate (cAMP)--dependent protein kinase dependent protein kinase

–– Epinephrine Epinephrine circulating in the blood in response to stress, circulating in the blood in response to stress, or or norepinephrinenorepinephrine released by neural connections to released by neural connections to adipose tissue, activates the cell membrane adeadipose tissue, activates the cell membrane ade--nylate nylate cyclase to produce cAMP. Thus, under conditions of stress or cyclase to produce cAMP. Thus, under conditions of stress or when neural signals indicate low levels of metabolic fuel, the when neural signals indicate low levels of metabolic fuel, the when neural signals indicate low levels of metabolic fuel, the when neural signals indicate low levels of metabolic fuel, the hormonehormone--sensitive lipase is activated.sensitive lipase is activated.

–– InsulinInsulin inhibits lipolysis by two mechanisms.inhibits lipolysis by two mechanisms.�� It reduces cAMP levels, probably by inhibiting adenylate cyclase It reduces cAMP levels, probably by inhibiting adenylate cyclase activity.activity.

�� It increases glucose entry into the adipocytes, so that the formation It increases glucose entry into the adipocytes, so that the formation of DHAP and glycerolof DHAP and glycerol--33--phosphate is increased. The availability of phosphate is increased. The availability of these products of glycolysis increases the rate of rethese products of glycolysis increases the rate of re--esterification of esterification of free fatty acids to triacylglycerols, thus reducing the rate of release free fatty acids to triacylglycerols, thus reducing the rate of release of the fatty acids from adipocytes. of the fatty acids from adipocytes.

–– ProstaglandinsProstaglandins inhibit lipolysis by reducing cAMP levels.inhibit lipolysis by reducing cAMP levels.

Enzymatic steps of lipolysisEnzymatic steps of lipolysis

�� Three different lipases are required to release the Three different lipases are required to release the three fatty acids from the triacylglycerols.three fatty acids from the triacylglycerols.–– HormoneHormone--sensitive triacylglycerol lipasesensitive triacylglycerol lipase converts converts

triacylglycerol to diacyltriacylglycerol to diacyl--glycerol plus a fatty acid.glycerol plus a fatty acid.–– Diacylglycerol lipaseDiacylglycerol lipase converts diacylglycerol to converts diacylglycerol to

monoacylglycerol plus a fatty acid.monoacylglycerol plus a fatty acid.monoacylglycerol plus a fatty acid.monoacylglycerol plus a fatty acid.–– Monoacylglycerol lipaseMonoacylglycerol lipase converts monoacylglycerol to converts monoacylglycerol to

glycerol plus a fatty acid.glycerol plus a fatty acid.

�� The rateThe rate--limiting step of lipolysis in limiting step of lipolysis in adipocytesadipocytes is the reaction catalyzed by the is the reaction catalyzed by the hormonehormone--sensitive triacylglycerol lipase. Diacylsensitive triacylglycerol lipase. Diacyl-- and and monoacylglycerol lipases are present in excess, so monoacylglycerol lipases are present in excess, so that once triacylglycerol lipase is activated, lipolysis that once triacylglycerol lipase is activated, lipolysis of triacylglycerols goes to completion.of triacylglycerols goes to completion.

Lipolysis in other tissuesLipolysis in other tissues

�� Triacylglycerols are stored mainly in Triacylglycerols are stored mainly in adipocytes. However, other tissues, adipocytes. However, other tissues, including muscle and liver, store small including muscle and liver, store small including muscle and liver, store small including muscle and liver, store small amounts of triacylglycerols as amounts of triacylglycerols as intracellular lipid droplets for their own intracellular lipid droplets for their own use. These fat stores appear to be use. These fat stores appear to be mobilized by hormonal controls similar mobilized by hormonal controls similar to those found in adipocytes.to those found in adipocytes.

KETONE BODY METABOLISMKETONE BODY METABOLISMKetone bodies (i.e., acetoacetate, Ketone bodies (i.e., acetoacetate, ββ--hydroxybutyrate, hydroxybutyrate, Ketone bodies (i.e., acetoacetate, Ketone bodies (i.e., acetoacetate, ββ--hydroxybutyrate, hydroxybutyrate, acetone) are the preferred energy substrates of the acetone) are the preferred energy substrates of the heart, skeletal muscle, and kidney during the fasting heart, skeletal muscle, and kidney during the fasting state. If blood levels of state. If blood levels of ββ--hydroxybutyrate and hydroxybutyrate and acetoacetate increase sufficiently, as they do during acetoacetate increase sufficiently, as they do during starvation, they also become the primary energy starvation, they also become the primary energy substrate for the brain.substrate for the brain.

Biosynthesis of ketone bodiesBiosynthesis of ketone bodies

�� Thiolase catalyzes the formation of two acetyl CoA Thiolase catalyzes the formation of two acetyl CoA molecules from acetoacetyl CoA.molecules from acetoacetyl CoA.

�� 33--HydroxyHydroxy--33--methylglutaryl CoA (HMG CoA) synthase methylglutaryl CoA (HMG CoA) synthase catalyzes the addition of another acetyl CoA to catalyzes the addition of another acetyl CoA to acetoacetyl CoA to form HMG CoA.acetoacetyl CoA to form HMG CoA.

�� HMG CoA lyase catalyzes the cleavage of HMG CoA to HMG CoA lyase catalyzes the cleavage of HMG CoA to acetoacetateacetoacetate and acetyl CoA.and acetyl CoA.acetoacetateacetoacetate and acetyl CoA.and acetyl CoA.

�� ββ--Hydroxybutyrate dehydrogenase catalyzes the Hydroxybutyrate dehydrogenase catalyzes the formation of formation of ββββββββ--hydroxybutyrate hydroxybutyrate from acetoacetate from acetoacetate when the NADH/NAD+ ratio is high, as it is in the liver when the NADH/NAD+ ratio is high, as it is in the liver during fasting.during fasting.

�� AcetoneAcetone is formed spontaneously from a small fraction is formed spontaneously from a small fraction of the circulating acetoacetate and is exhaled by the of the circulating acetoacetate and is exhaled by the lungs. In patients with untreated diabetes, the odor of lungs. In patients with untreated diabetes, the odor of acetone is apparent on the patient's breath.acetone is apparent on the patient's breath.

Formation of Ketone BodiesFormation of Ketone Bodies

�� The Ketone bodiesThe Ketone bodies--acetoacetate, dacetoacetate, d--33--hydroxybutyrate, and acetone hydroxybutyrate, and acetone from acetyl CoAfrom acetyl CoA——are formed primarily in the liver. Enzymes catalyzing are formed primarily in the liver. Enzymes catalyzing these reactions are (1) 3these reactions are (1) 3--ketothiolase, (2) hydroxymethylglutaryl CoA ketothiolase, (2) hydroxymethylglutaryl CoA synthase, (3) hydroxymethylglutaryl CoA cleavage enzyme, and (4) dsynthase, (3) hydroxymethylglutaryl CoA cleavage enzyme, and (4) d--33--hydroxybutyrate dehydrogenase. Acetoacetate spontaneously hydroxybutyrate dehydrogenase. Acetoacetate spontaneously decarboxylates to form acetone.decarboxylates to form acetone.

Ketone body oxidationKetone body oxidation

�� A 3A 3--keto acid CoA transferaseketo acid CoA transferase catalyzes the formation catalyzes the formation of the CoA thioester of acetoacetate. This is a of the CoA thioester of acetoacetate. This is a nonhepatic nonhepatic enzymeenzyme that prevents ketone bodies from being used as that prevents ketone bodies from being used as an energy source by the liver.an energy source by the liver.

�� ThiolaseThiolase catalyzes the cleavage of acetoacetyl CoA to two catalyzes the cleavage of acetoacetyl CoA to two acetyl CoA molecules with the use of CoA, providing twoacetyl CoA molecules with the use of CoA, providing two--carbon fragments for oxidation by the citric acid cycle.carbon fragments for oxidation by the citric acid cycle.

�� Energy yield from oxidation of ketone bodiesEnergy yield from oxidation of ketone bodies�� Energy yield from oxidation of ketone bodiesEnergy yield from oxidation of ketone bodies–– Each mole of acetyl CoA that is formed yields 12 moles of ATP via Each mole of acetyl CoA that is formed yields 12 moles of ATP via the citric acid cycle, electron transport, and oxidative the citric acid cycle, electron transport, and oxidative phosphorylation.phosphorylation.

–– Conversion of Conversion of ββ--hydroxybutyrate to acetoacetate yields an NADH hydroxybutyrate to acetoacetate yields an NADH molecule, which in turn yields three more ATP molecules by molecule, which in turn yields three more ATP molecules by electron transport and oxidative phosphorylation.electron transport and oxidative phosphorylation.

–– The activation reaction requires the equivalent of 1 mole of ATP.The activation reaction requires the equivalent of 1 mole of ATP.–– Therefore, Therefore, oxidation of acetoacetate yields 23 moles of ATP; oxidation of acetoacetate yields 23 moles of ATP; oxidation of oxidation of ββββββββ--hydroxybutyrate yields 26 moles of ATPhydroxybutyrate yields 26 moles of ATP

CH

OH

CH3

CH2

COOH

3-hydroxybutirate

NAD+

NADH+H+

hydroxybutirate-dehydrohenase

CH3

C

O

CH2

C

O

OH

Acetoacetate

Succenyl-CоА

Succinate

SuccinylCоА-acetoacetate-CоА-transferase

Keton body oxidation

CH3

C

O

CH2

C

O

SCoA

Acetoacetyl-CоА

HSCoA

Thiolase

CH3 C

O

SCoA

CH3 C

O

SCoA

+

2 Acetyl-CоА

Citric cycle

STEROIDSSTEROIDS

are lipids that contain four fused are lipids that contain four fused carbon rings that form the carbon rings that form the cyclopentanoperhydrophenanthrene cyclopentanoperhydrophenanthrene steroid nucleus.steroid nucleus.

�� CholesteroCholesterol l is the major is the major sterolsterol in the human in the human body. Sterols are a class of steroids characterized body. Sterols are a class of steroids characterized by a hydroxyl group at carbon 3, and an aliphatic by a hydroxyl group at carbon 3, and an aliphatic chain of at least eight carbons at Cchain of at least eight carbons at C--17.17.

�� Cholesterol is a Cholesterol is a structural componentstructural component of cell of cell membranes and plasma lipoproteins.membranes and plasma lipoproteins.

�� It It is the is the precursorprecursor from which steroid hormones from which steroid hormones and bile acids are synthesized.and bile acids are synthesized.

�� Steroid hormonesSteroid hormones produced in humans are produced in humans are formed and secreted by the formed and secreted by the adrenal cortex, the adrenal cortex, the testis, the ovarytestis, the ovary, , and the and the placentaplacenta..formed and secreted by the formed and secreted by the adrenal cortex, the adrenal cortex, the testis, the ovarytestis, the ovary, , and the and the placentaplacenta..

�� Primary bile acidsPrimary bile acids. . Cholic and Cholic and chenodeoxycholic acids are formed in the liver chenodeoxycholic acids are formed in the liver from cholesterolfrom cholesterol

Biosynthesis of cholesterolBiosynthesis of cholesterol

�� The The liver is the major siteliver is the major site of cholesterol of cholesterol biosynthesis, although other tissues also are biosynthesis, although other tissues also are active in this regard (e.g., the intestines, active in this regard (e.g., the intestines, active in this regard (e.g., the intestines, active in this regard (e.g., the intestines, adrenal glands, gonads, skin, neural tissue, adrenal glands, gonads, skin, neural tissue, and aorta). and aorta).

�� All 27 carbon atoms of cholesterol are All 27 carbon atoms of cholesterol are derived from the acetate moiety of acetyl derived from the acetate moiety of acetyl CoA, and the enzymes reside in the cytosolic CoA, and the enzymes reside in the cytosolic and microsomal fractions.and microsomal fractions.

�� 33--HydroxyHydroxy--33--methylglutaryl CoA (HMG methylglutaryl CoA (HMG CoA)CoA) is formed in the cytosol from acetyl CoA is formed in the cytosol from acetyl CoA in two steps by in two steps by thiolase and HMG CoA thiolase and HMG CoA synthasesynthase..

HMG CoA is converted to HMG CoA is converted to mevalonate by HMG mevalonate by HMG CoA reductaseCoA reductase, an NADPH, an NADPH--dependent enzyme. dependent enzyme. This is the This is the key regulatory sitekey regulatory site of cholesterol of cholesterol biosynthesisbiosynthesis

�� This is regarded as the This is regarded as the raterate--limiting step in limiting step in cholesterol biosynthesis.cholesterol biosynthesis. Although later steps Although later steps may be affected by a prolonged stimulus (e.g., may be affected by a prolonged stimulus (e.g., longlong--term feeding of cholesterol), their rates term feeding of cholesterol), their rates never become lower than that of HMG CoA never become lower than that of HMG CoA reductase.reductase.

�� The feeding of cholesterol reduces the hepatic The feeding of cholesterol reduces the hepatic biosynthesis of cholesterol by reducing the biosynthesis of cholesterol by reducing the activity of HMG CoA reductase. Importantly, activity of HMG CoA reductase. Importantly, intestinal cholesterol biosynthesis does not intestinal cholesterol biosynthesis does not activity of HMG CoA reductase. Importantly, activity of HMG CoA reductase. Importantly, intestinal cholesterol biosynthesis does not intestinal cholesterol biosynthesis does not respond to the feeding of highrespond to the feeding of high--cholesterol diets.cholesterol diets.

�� HMG CoA reductase activity also is reduced by HMG CoA reductase activity also is reduced by fasting, which limits the availability of acetyl CoA fasting, which limits the availability of acetyl CoA and NADPH for cholesterol biosynthesis.and NADPH for cholesterol biosynthesis.

�� HMG CoA reductase undergoes reversible HMG CoA reductase undergoes reversible phosphorylationphosphorylation--dephosphorylation; the dephosphorylation; the phosphorylated enzyme is less active than the phosphorylated enzyme is less active than the dephosphorylated form.dephosphorylated form.

Hormonal effects on Hormonal effects on cholesterol biosynthesischolesterol biosynthesis

�� InsulinInsulin stimulates HMG CoA stimulates HMG CoA reductase activity.reductase activity.reductase activity.reductase activity.

�� GlucagonGlucagon antagonizes the effect of antagonizes the effect of insulin.insulin.

�� Thyroid hormoneThyroid hormone stimulates HMG stimulates HMG CoA reductase. CoA reductase.

The drug lovastatin, which The drug lovastatin, which is used to treat is used to treat hypercholesterolemia, hypercholesterolemia, blocks endogenous blocks endogenous blocks endogenous blocks endogenous cholesterol synthesis by cholesterol synthesis by inhibiting HMG CoA inhibiting HMG CoA reductasereductase

�� Mevalonate is activated with highMevalonate is activated with high--energy energy phosphate bonds and then decarboxylated to phosphate bonds and then decarboxylated to form the fiveform the five--carbon isoprenoid isomers, carbon isoprenoid isomers, 3,33,3--dimethylallyl pyrophosphate and dimethylallyl pyrophosphate and isopentenyl pyrophosphateisopentenyl pyrophosphate. . An isomerase An isomerase governs an equilibrium between these isomers.governs an equilibrium between these isomers.

�� A molecule of 3,3A molecule of 3,3--dimethylallyl pyrophosphate dimethylallyl pyrophosphate condenses with a molecule of isopentenyl condenses with a molecule of isopentenyl condenses with a molecule of isopentenyl condenses with a molecule of isopentenyl pyrophosphate to form the 10pyrophosphate to form the 10--carbon compound carbon compound geranyl pyrophosphategeranyl pyrophosphate..

�� Another molecule of isopentenyl pyrophosphate Another molecule of isopentenyl pyrophosphate reacts with geranyl pyrophosphate to form the reacts with geranyl pyrophosphate to form the 1515--carbon compound carbon compound farnesyl pyrophosphatefarnesyl pyrophosphate, , which is also a precursor for ubiquinonewhich is also a precursor for ubiquinone..

�� Squalene synthaseSqualene synthase catalyzes the catalyzes the NADPHNADPH--dependent conversion of two dependent conversion of two molecules of farnesyl pyrophosphate molecules of farnesyl pyrophosphate to to squalenesqualene..

�� Squalene is converted to Squalene is converted to squalene squalene 2,32,3--epoxideepoxide by an NADPHby an NADPH--2,32,3--epoxideepoxide by an NADPHby an NADPH--dependent monooxygenase.dependent monooxygenase.

�� A cyclaseA cyclase catalyzes the cyclization of catalyzes the cyclization of squalene to form lanosterol, which squalene to form lanosterol, which also is a precursor for the synthesis of also is a precursor for the synthesis of vitamin D.vitamin D.

Lanosterol is converted to Lanosterol is converted to cholesterolcholesterol by a by a series of reactions that result in the removal of series of reactions that result in the removal of three methyl groups and rearrangement of three methyl groups and rearrangement of double bondsdouble bonds

Esterification of cholesterolEsterification of cholesterol

�� The bulk of the cholesterol in tissues and approximately The bulk of the cholesterol in tissues and approximately 65% of plasma cholesterol is esterified with long65% of plasma cholesterol is esterified with long--chain chain fatty acids at Cfatty acids at C--3.3.

�� The synthesis of cellular cholesterol ester requires ATP to The synthesis of cellular cholesterol ester requires ATP to form fatty acyl CoA derivatives, which are then form fatty acyl CoA derivatives, which are then form fatty acyl CoA derivatives, which are then form fatty acyl CoA derivatives, which are then transferred to the 3transferred to the 3--ββ--hydroxyl group of cholesterol.hydroxyl group of cholesterol.

�� Cholesterol associated with plasma lipoproteins can be Cholesterol associated with plasma lipoproteins can be esterified by esterified by lecithin:cholesterol acyltransferaselecithin:cholesterol acyltransferase..

Phosphatidylcholine + Cholesterol Phosphatidylcholine + Cholesterol →→Lysophosphatidylcholine + Cholesterol fatty acyl esterLysophosphatidylcholine + Cholesterol fatty acyl ester

Bile acidsBile acids�� Bile acids are Bile acids are synthesized synthesized from cholesterol from cholesterol in in the liver and stored in the gallbladder.the liver and stored in the gallbladder.

�� Enterohepatic circulationEnterohepatic circulation–– After release of bile acids from storage in the After release of bile acids from storage in the gallbladder to the intestine, the two primary bile gallbladder to the intestine, the two primary bile acidsacids——cholic and chenodeoxycholiccholic and chenodeoxycholic——are converted are converted in part to the secondary bile acidsin part to the secondary bile acids——deoxycholate deoxycholate in part to the secondary bile acidsin part to the secondary bile acids——deoxycholate deoxycholate and lithocholateand lithocholate——by intestinal bacteria.by intestinal bacteria.

–– In the intestine, both primary and secondary bile In the intestine, both primary and secondary bile acids are deconjugated, reabacids are deconjugated, reab--sorbed by the sorbed by the intestinal mucosa, and returned to the liver bound to intestinal mucosa, and returned to the liver bound to serum albumin via the portal vein.serum albumin via the portal vein.

–– The liver takes up the bile acids, reconjugates them The liver takes up the bile acids, reconjugates them with taurine or glycine, and secretes them in the with taurine or glycine, and secretes them in the bile.bile.

�� Secretion of bile into the intestine is the Secretion of bile into the intestine is the main route for the excretion of main route for the excretion of cholesterolcholesterol because the steroid nucleus because the steroid nucleus cannot be oxidized to carbon dioxide and cannot be oxidized to carbon dioxide and water by human tissues.water by human tissues.

�� Solubility of cholesterol in bileSolubility of cholesterol in bile–– Bile contains a considerable amount of Bile contains a considerable amount of cholesterol, which would be insoluble except for cholesterol, which would be insoluble except for its association with bile salts and phospholipids its association with bile salts and phospholipids its association with bile salts and phospholipids its association with bile salts and phospholipids (chiefly phosphatidylcholine).(chiefly phosphatidylcholine).

–– Despite the presence of these solubilizing agents, Despite the presence of these solubilizing agents, an increased concentration of cholesterol in the an increased concentration of cholesterol in the bile can lead to the formation of bile can lead to the formation of gallstones gallstones in in the gallbladder or duct. These are formed if the gallbladder or duct. These are formed if cholesterol is precipitated out of solution around cholesterol is precipitated out of solution around a core of protein and bilirubin, which is a a core of protein and bilirubin, which is a condition known as condition known as cholelithiasis.cholelithiasis.