lipolysis, fat mobilization, fatty acid (beta, alpha, omega) oxidation, ketogenesis.pdf

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Lipolysis and the Oxidation of Fatty Acids

Introduction

Mobilization of Fat Stores

Cellular Uptake of Fatty Acids

Roles of Fatty Acid Binding Proteins, FABP

Mitochondrial (beta) -Oxidation ReactionsMinor Alternative Fatty Acid Oxidation Reactions

Peroxisomal (beta) -Oxidation Reactions

Microsomal (omega) -Oxidation Reactions

Phytanic Acid (alpha) -Oxidation Reactions

Regulation of Fatty Acid Metabolism

The Glucose-Fatty Acid Cycle

Clinical Aspects of Fatty Acid Metabolism

Ketogenesis

Diabetic Ketoacidosis

Regulation of Ketogenesis

Clinical Significance of Ketogenesis

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Introduction

Utilization of dietary lipids requires that they first be absorbed through the intestine. As

these molecules are oils they would be essentially insoluble in the aqueous intestinal

environment. Solubilization (emulsification) of dietary lipid is accomplished initially via the

agitation action as food passes through the stomach and then continues within the intestine via

bile saltsthat are synthesized in the liver and secreted from the gallbladder.

The emulsified fats can then be degraded by salivary, gastric and pancreatic lipases. The

lipases found in the gastrointestinal tract include lingual lipase (secreted by the serous glands

of the tongue), gastric lipase (secreted by chief cells of the stomach), pancreatic lipase, and

pancreatic lipase-related proteins 1 and 2. These enzymes generate free fatty acids and a

mixture of mono- and diacylglycerols from dietary triacylglycerols. Pancreatic lipase degrades

triacylglycerols at the 1 and 3 positions sequentially to generate 1,2-diacylglycerols and 2-

acylglycerols. Phospholipids are degraded at the 2 position by pancreatic phospholipase A2releasing a free fatty acid and the lysophospholipid.

Following absorption of the products of pancreatic lipase by the intestinal mucosal cells,

the resynthesis of triacylglycerides occurs. The triacylglycerides are then solubilized in

lipoprotein complexes(complexes of lipid and protein) called chylomicrons. A chylomicron

contains lipid droplets surrounded by the more polar lipids and finally a layer of proteins.

Triacylglycerides synthesized in the liver are packaged into VLDLs and released into the blood

directly. Chylomicrons from the intestine are then released into the blood via the lymph system

for delivery to the various tissues for storage or production of energy through oxidation.

The triacylglyceride components of VLDLs and chylomicrons are hydrolyzed to free fatty

acids and glycerol in the capillaries of tissues such as liver, adipose tissue and skeletal

muscle by the actions of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL). The

free fatty acids are then absorbed by the cells and the glycerol is returned via the blood to the

liver (principal site) and kidneys. The glycerol can then converted to the glycolytic intermediate

dihydroxyacetone phosphate DHAP or phosphorylated by glycerol kinase to glycerol-3-phosphate for reuse in triglyceride synthesis.

The classification of blood lipids is distinguished based upon the density of the different

lipoproteins. As lipid is less dense than protein, the lower the density of lipoprotein the less

protein there is.
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Biochemistry Clinical Medical Enzyme Deficiency Fatty Acids
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Additional proteins associated with lipid droplets (LD) in adipocytes participate in the CGI-58-mediated regulation

of ATGL. In resting adipocytes of both WAT and BAT, the LD protein perilipin-1 interacts with CGI-58, preventing its

binding to and, induction of ATGL. Following -adrenergic stimulation of WAT, PKA phosphorylates perilipin-1 at

multiple sites resulting in the release of CGI-58 which in turn, binds and stimulates ATGL. This demonstrates that -

adrenergic stimulation of PKA induces ATGL activity, not by direct phosphorylation of ATGL itself, but through

phosphorylation of perilipin-1. This model of ATGL regulation is evident from frameshift mutants that have been

identified in human perilipin-1. These mutations are identified as V398fs and L404fs indicating that the frame shift

occurs at valine 398 and leucine 404, respectively. Each of these mutant ATGL proteins fail to bind CGI-58, resulting in

unrestrained lipolysis, partial lipodystrophy, hypertriglyceridemia, and insulin resistance.

In non-adipose tissues with high rates of TG hydrolysis, such as skeletal muscle and liver, regulation of ATGL

activity occurs via a mechanism distinct from that in adipose tissues. In these tissues, perilipin-1 is replaced byperilipin-5. During fasting, perilipin-5 recruits both ATGL and CGI-58 to LDs by direct binding of the enzyme and its

coactivator. Data indicates that perilipin-5 is involved in the interaction of LDs with mitochondria and thereby inhibits

ATGL-mediated TG hydrolysis. Other perilipins exist in cells including perilipin-2, -3, and -4 but it is unclear if these

proteins are also involved in regulating the association of ATGL with LDs. In hepatocyte cell lines it has been shown

that overexpression of perilipin-2 inhibits ATGL activity by restricting its physical access to LDs.

Recently, a specific peptide inhibitor for ATGL was isolated from white blood cells, specifically mononuclear cells.

This peptide was originally identifed as being involved in the regulation of the G0to G1transition of the cell cycle. This

peptide was, therefore, called G0G1 switch protein 2 (G0S2). The protein is found in numerous tissues, with highest

concentrations in adipose tissue and liver. In adipose tissue G0S2 expression is very low during fasting but increases

after feeding. Conversely, fasting or PPAR-agonists increase hepatic G0S2 expression. The protein has been shown

to localize to LDs, cytoplasm, ER, and mitochondria. These different subcellular localizations likely relate to multiple

functions for G0S2 in regulating lipolysis, the cell cycle, and, possibly, apoptosis via its ability to interact with the

mitochondrial antiapoptotic factor Bcl-2. With respect to ATGL regulation, the binding of the enzyme to LDs andsubsequent is dependent on a physical interaction between the N-terminal region of G0S2 and the patatin domain of

ATGL.

The delivery of ATGL to LDs requires functional vesicular transport. When essential protein components of the

transport machinery are defective or missing, such as ADP-ribosylation factor 1 (ARF1), small GTP-binding protein 1

(SAR1), the guanine-nucleotide exchange factor Golgi-Brefeldin A resistance factor (GBF1), or the coatamer protein

coat-complex I (COPI) and COPII, ATGL translocation to LDs is blocked and the enzyme remains associated with the

ER.

Hormone-sensitive lipase: HSL

A landmark study published in 1964 demonstrated that a lipolytic activity present in adipose tissue was induced by

hormonal stimulation. This work described the isolation and characterization of both HSL and monoacylglyceride

lipase (MGL). This original study demonstrated that HSL had a higher level of activity as a DG hydrolase than as a TG

hydrolase. Nevertheless, it became dogma that HSL was rate-limiting for the catabolism of fat stores in adipose andmany non-adipose tissues. However, when HSL-deficient mice were produced and shown to efficiently hydrolyze TGs

the model began to emerge demonstrating ATGL, and not HSL, to be rate-limiting for adipose tissue TG hydrolysis.

HSL-deficient mice do not accumulate TGs in either adipose or non-adipose tissues, but they do accumulate large

amounts of DGs in many tissues. This indicated for the first time that HSL was more important as a DG hydrolase than

a TG hydrolase. It is now accepted that ATGL is responsible for the initial step of lipolysis in human adipocytes, and

that HSL is rate-limiting for the catabolism of DGs. HSL not only hydrolyzes DGs but is also active at hydrolyzing ester

bonds of many other lipids including TGs, MGs, cholesteryl esters, retinyl esters, and short-chain carbonic acid esters.

The HSL gene is located on chromosome 19q13.2. Alternative exon useage results in tissue-specific differences

in mRNA and protein size. In adipose tissue the HSL protein is composed of 775 amino acids, whereas the testicular

form is composed of 1,076 amino acids. The expression profile of HSL essentially mirrors that of ATGL. Highest

mRNA and protein concentrations are found in WAT and BAT with low levels of expression found in muscle, testis,

steroidogenic tissues, and pancreatic islets as well as several other tissues. Functional studies on the enzyme have

identified an N-terminal lipid-binding region, the / hydrolase fold domain including the catalytic triad, and theregulatory module containing all known phosphorylation sites important for regulation of enzyme activity.
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Model for the activation of adipose tissue hormone-sensitive lipase:Epinephrine binding to -adrenergic

receptors or glucagon binding its GPCR triggers activation of the associate Gs-type G-protein that in turn leads to

the activation of adenylate cyclase. The resultant increase in cAMP activates PKA which then phosphorylates and

activates hormone-sensitive lipase (HSL). Hormone-sensitive lipase hydrolyzes fatty acids from diacylglycerols that

result from the action of ATGL/desnutrin. The final fatty acid is released from monoglycerides through the action ofmonoglyceride lipase (MGL), an enzyme that is also active in the absence of hormonal stimulation.

HSL and ATGL share many regulatory similarities yet the mechanisms of the regulatory processes differ markedly

between the two enzymes. In adipose tissue, HSL enzyme activity is strongly induced by -adrenergic stimulation,

conversely insulin has a strong inhibitory effect. While -adrenergic stimulation regulates ATGL primarily via

recruitment of the coactivator CGI-58), HSL is a major target for PKA-mediated phosphorylation. Additional kinases,

including AMPK, extracellular signal-regulated kinase (ERK), glycogen synthase kinase-4 (GSK-4), and

Ca2+/calmodulin-dependent kinase 1 (CAMK1), also phosphorylate HSL to modulate the activity of the enzyme. HSL

has at least five potential phosphorylation sites, of which S660 and S663 appear to be particularly important for

hydrolytic activity. Enzyme phosphorylation affects enzyme activity only moderately resulting in an approximate 2-fold

increase in hydrolytic activity. For full activation, HSL must gain access to LDs, which, in adipose tissue, is mediated

by perilipin-1. In addition to phosphorylating HSL, PKA also phosphorylates perilipin-1 on six consensus serine

residues. The result of these phosphorylations is the binding of HSL to the N-terminal region of perilipin-1. This protein-

protein interaction is the means by which HSL gains access to LDs. The net effect, of HSL-phosphorylation andenzyme translocation to LDs, coupled with ATGL activation by CGI-58, leads to a more than 100-fold increase in TG

hydrolysis in adipocytes.

Additional factors modulate the activation of HSL and ATGL. One such factor is receptor-interacting protein 140

(RIP-140) which induces lipolysis by binding to perilipin-1, increasing HSL translocation to LDs, and activating ATGL

via CGI-58 dissociation from perilipin-1. In non-adipose tissues, such as skeletal muscle, HSL is activated by

phosphorylation in response to epinephrine (-adrenergic receptor-mediated activation of PKA) and muscle

contraction (calcium release from sarcoplasmic reticulum). Since skeletal muscles lack perilipin-1 it has not yet been

determined which alternative mechanisms regulate HSL access to LDs.

Insulin-mediated deactivation of lipolysis is associated with transcriptional downregulation of ATGL and HSL

expression. Additionally, insulin signaling results in phosphorylation and activation of various phosphodiesterase

(PDE) isoforms by PKB/Akt leading to PDE-catalyzed hydrolysis of cAMP which in turn results in reduced activation of

PKA. These actions turn off lipolysis by preventing phosphorylation of both HSL and perilipin-1, activation and

translocation of HSL, and activation of ATGL by CGI-58. In addition to its peripheral action, insulin also functions within

the sympathetic nervous system to inhibit lipolysis in WAT. Increased insulin levels in the brain inhibit HSL and perilipin

phosphorylation which results in reduced HSL and ATGL activities.

Monoacylglyceride lipase: MGL

MGL is considered to be the rate-limiting enzyme for the breakdown of MGs that are the result of both extracellular


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Medical Transport A Fatty Liver Fat Metabolism Liver Enzyme
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FATP6 levels in the heart; protein only detected in heart and testis; exhibits a preference for the transport of

palmitic acid and linoleic acid, does not transport fatty acids less than 10 carbons long; located on

chromosome 5q23.3 spanning 67 kb and composed of 11 exons encoding a 619 amino acidprotein

The result of the interaction of fatty acids with plasma membrane receptors/binding proteins is a transmembrane

concentration gradient. At the plasma membrane the apparent pKa of the fatty acid shifts from about 4.5 in aqueous

solutions to about 7.6. This pKa change is independent of fatty acid type. As a consequence, about half of the fatty

acids are present in the un-ionized form. This local environment effect promotes a transfer (flip-flop) of uncharged fatty

acids from the outer leaflet across the phospholipid bilayer. At the cytosolic surface of the plasma membrane, fatty

acids can associate with the cytosolic fatty acid binding protein (FABPc) or with caveolin-1. Caveolin-1 is a constituent

of caveolae (Latin for little caves) which are specialized "lipid rafts" present in flask-shaped indentations in the plasma

membranes of many cells types that perform a number of signaling functions by serving as lipid delivery vehicles for

subcellular organelles. In order that the fatty acids that are thus taken up to be directed to the various metabolic

pathways (e.g. oxidation or triglyceride synthesis) they must be activated to acyl-CoA. Members of the atty acid

transport protein (FATP) family have been shown to possess acyl-CoA synthetase (ACS) activity. Activation of fatty

acids by FATPs occurs at the highly conserved cytosolic AMP-binding site of these proteins. The overall process of

cellular fatty acid uptake and subsequent intracellular utilization represents a continuum of dissociation from albumin by

interaction with the membrane-associated transport proteins, binding to FABPc and caveolin-1 at the cytosolic plasma

membrane, activation to acyl-CoA (in many cases via FATP action) followed by intracellular trafficking via FABPcand/or caveolae to si tes of metabolic disposition.

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Roles of Intracellular Fatty Acid Binding Proteins, FABPFatty acid binding proteins (FABPs) represent a family of intracellular lipid-binding proteins whose functions are to

reversibly bind intracellular hydrophobic ligands and transport the bound ligand throughout the various cellular

compartments, including the peroxisomes, mitochondria, endoplasmic reticulum and nucleus. FABPs have broad

binding characteristics which includes the ability to bind long-chain (C16C20) fatty acids (LCFAs), eicosanoids, bile

salts and peroxisome proliferators. There are currently nine well characterized FABP genes in the human genome.

Each of these FABPs was originally named for the tissue in which it was first isolated and characterized or in which it

predominates. However, many of these FABPs are expressed in numerous tissues.

Expression of a particular FABP gene directly reflects the lipid metabolic capacity of that tissue. In high lipid

metabolizing tissues, such as the liver, adipose tissue, and the heart, the expressed FABPs can account for 1%5%

per cent of total soluble cytosolic proteins. The expression of FABPs in the cell is essential for the binding of

hydrophobic ligands, particularly free fatty acids, in order to reduce the detergent-like properties of high concentrations

of fatty acids, thereby keeping them soluble. FABPs are critical to the process of lipid trafficking within cells to thevarious cellular compartments where they will be stored, oxidized, utilized for membrane synthesis, and for their roles in

the activation of nuclear receptors. With respect to the latter function, it has been shown that FABPs are involved in the

targeting of fatty acids to transcription factors of the peroxisome proliferator-activated receptor (PPAR) family. In

addition to their importance in intracellular lipid trafficking, many FABPs interact with phospholipid-rich membranes

and bind eicosanoid intermediates protecting these substrates against peroxidation strongly implicating these proteins

in antioxidant-type behaviour.

FABP Alternate NamesTissue

LocationFunctions / Comments

FABP1

(L-FABP)

Z protein, hepatic

FABP, heme-binding

protein

liver, intestine,

pancreas, kidney,

lung, stomach

represents up to 5% of hepatocyte cytosolic protein;

unique ability to bind multiple ligands at once; in

addition to various free fatty acids FABP1 binds bindsfatty acyl-carnitines, intermediates in glyceride

synthesis, lysophospholipids, cholesterol, bile acids,

prostaglandins, lipoxygenase products, retinoids,

heme and bilirubin; FABP1 also binds numerous

xenobiotic drugs such as NSAIDs, fibrates, beta

blockers, and benzodiazepines

FABP2

(I-FABP) gut FABP, gFABP intestine, livermediates dietary fat absorption of free long-chain fatty

acids (LCFAs)

FABP3

(H-FABP)

O-FABP, mammary-

derived growth

inhibitor, MDGI

skeletal and heart

muscle, brain,

kidney, lung,stomach, testes,

placenta, ovary,

brown adipose

tissue (BAT),

adrenal glands,

mammary glands

makes up 4%8% of cytosolic protein in the heart;

major function is to traffic fatty acids to the

mitochondria for oxidaiton; also binds non-prostanoidoxygenated fatty aicds; measurement of protein in the

blood is considered an early marker for myocardial

infarct; may also be a marker for CreutzfeldtJakob

disease (CJD) by measurement of levels in the

cerebrospinal fluid
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FABP4

(A-FABP)

adipocyte protein 2,

aP2

adipocytes and

macrophages of

adipose tissue,

dendritic cells

specific binding capacity for LCFAs; is a marker for

adipocyte maturation; modulates the activity of HSL

through direct interaction; macrophage FABP4

modulates inflammatory responses; recently

demonstrated to be a secreted adipokine involved in

regulating hepatic glucose production

FABP5

(E-FABP)

psoriasis-associated

FABP (PA-FABP);

keratinocyte-type

FABP (KFABP)

skin, brain,

stomach,

intestines,kidney, liver, lung,

heart, skeletal

muscle, tongue,

adipocytes,

macrophages,

dendritic cells,

testes, retina,

placenta, spleen

physiological ligands not completely determined; in

vitrothe protein binds stearic acid with high affinity

while having reduced affinity for unsaturated fatty

acids; interacts with HSL like FABP3

FABP6

(Il-FABP)

ileal lipid-binding

protein (ILBP);

gastrotropin;

intestinal bile acid-

binding protein (I-BABP)

ileum, stomach,

adrenal glands,

ovary

involved in enterohepatic circulation of bile acids;

binds bile acids with highest affinity then fatty acids;

interacts with the ileal bile acid transporter protein

FABP7

(B-FABP)

brain lipid-binding

protein (BLBP)

brain, glial cells,

mammary

glands, retina

grey matter neurons do not express FABP7; highest

affinity for long-chain omega-3 polyunsaturated fatty

acids (PUFAs) particularly EPA and DHA; also binds

oleic acid and arachidonic acid but does not bind

palmitic acid or retinoic acid

FABP8

(M-FABP)

peripheral myelin

protein 2 (PMP2)

Schwann cells,

peripheral

nervous system

binds LCFAs; thought to be involved in stabilizing

myelin membranes

FABP9(T-FABP)

testes lipid-bindingprotein (TLBP);

testes, mammaryglands, salivary

glands

precise functions not clearly defined; thought to beinvolved in protection of fatty acids in sperm from

oxidation

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Mitochondrial (beta) -Oxidation Reactions

Oxidation of fatty acids occurs in the mitochondria and the peroxisomes (see below). Fatty acids of between 48

and between 612 carbon atoms in length, referred to as short- and medium-chain fatty acids (SCFAs and MCFAs,

respectively), are oxidized exclusively in the mitochondria. Long-chain fatty acids (LCFAs: 1016 carbons long) are

oxidized in both the mitochondria and the peroxisomes with the peroxisomes exhibiting preference for 14-carbon andlonger LCFAs. Very-long-chain fatty acids (VLCFAs: C17C26) are preferentially oxidized in the peroxisomes.

Fatty acids must be activated in the cytoplasm before being oxidized in the mitochondria. Activation is catalyzed

by fatty acyl-CoA synthetases (also called acyl-CoA ligases or thiokinases). The net result of this activation process is

the consumption of 2 molar equivalents of ATP.

Fatty acid + ATP + CoA > Acyl-CoA + PPi+ AMP

The transport of fatty acyl-CoA into the mitochondria is accomplished via an acyl-carnitine intermediate, which

itself is generated by the action of carnitine palmitoyltransferase 1 (CPT-1 or CPT-I) an enzyme that resides in the

outer mitochondrial membrane. There are three CPT-1 genes in humans identified as CPT-1A, CPT-1B, and CPT-1C.

Expression of CPT-1A predominates in the liver and is thus, referred to as the liver isoform. CPT-1B expression

predominates in skeletal muscle and is thus, referred to as the muscle isoform. CPT-1C expression is exclusive to the

brain and testes. The CPT-1A gene (symbol = CPT1A) is located on chromosome 11q13.3 and consists of 20 exons

spanning 60 kb encoding a 773 amino acid protein. The CPT-1B gene (symbol = CPT1B) is located on chromosome

22q13.33 and consists of 21 exons spanning 10 kb. The CPT-1C gene (symbol = CPT1C) is located on chromosome

19q13.3 and consists of 20 exons spanning 23 kb. The activity of CPT-1C is distinct from those of CPT-1A and CPT-

1B in that it does not act on the same types of fatty acyl-CoAs that are substrates for the latter two enzymes. However,

CPT-1C does exhibit high-affinity malonyl-CoA binding.

Following carnitine acyl-carnitine-mediated transfer of the CPT-1-generated fatty acyl-carnitines across the inner
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mitochondrial membrane, the fatty acyl-carnitine molecules are acted on by the inner mitochondria membrane carnitine

palmitoyltransferase 2 (CPT-2 or CPT-II) regenerating the fatty acyl-CoA molecules. The CPT-2 gene (symbol = CPT2)

is located on chromosome 1p32.3 and consists of 5 exons that span 20 kb.

Transport of fatty acids from the cytoplasm to the inner mitochondrial space for oxidation. Following activation to

a fatty-CoA, the CoA is exchanged for carnitine by CPT-1. The fatty-carnitine is then transported to the inside of the

mitochondrion where a reversal exchange takes place through the action of CPT-2. Once inside the mitochondrion

the fatty-CoA is a substrate for the -oxidation machinery.

The process of mitochondrial fatty acid oxidation is termed -oxidation since it occurs through the sequential

removal of 2-carbon units by oxidation at the -carbon position of the fatty acyl-CoA molecule. The oxidation of fattyacids and lipids in the peroxisomes (see below) also occurs via a process of -oxidation. Each round of -oxidation

involves four steps that, in order, are oxidation, hydration, oxidation, and cleavage.

The first oxidation step in mitochondrial -oxidation involves a family of FAD-dependent acyl-CoA

dehydrogenases. Each of these dehydrogenases has a range of substrate specificity determined by the length of the

fatty acid. Short-chain acyl-CoA dehydrogenase (SCAD, also called butyryl-CoA dehydrogenase) prefers fats of 46

carbons in length; medium-chain acyl-CoA dehydrogenase (MCAD) prefers fats of 416 carbons in length with

maximal activity for C10 acyl-CoAs; long-chain acyl-CoA dehydrogenase (LCAD) prefers fats of 616 carbons in

length with maximal activity for C12 acyl-CoAs.

The next three steps in mitochondrial -oxidation involve a hydration step, another oxidation step, and finally a

hydrolytic reaction that requires CoA and releases acetyl-CoA and an acy-CoA two carbon atoms shorter than the

initial substrate. The water addition is catalyzed by an enoyl-CoA hydratase activity, the second oxidation step is

catalyzed by an NAD-dependent long-chain hydroxacyl-CoA dehydrogenase activity (3-hydroxyacyl-CoA

dehydrogenase activity), and finally the cleavage into an acyl-CoA and an acetyl-CoA is catalyzed by a thiolase activity.These three activities are encoded in a multifunctional enzyme called the mitochondrial trifunctional protein, MTP. MTP

is composed of eight protein subunits, four -subunits encoded by the HADHA gene and four -subunits encoded by

the HADHB gene. The -subunits contain the enoyl-CoA hydratase and long-chain hydroxyacyl-CoA dehydrogenase

activities, while the -subunits possess the 3-ketoacyl-CoA thiolase (-ketothiolase or just thiolase) activity. The

mammalian genome actually encodes five distinct enzymes with thiolase activity.

Mammalian Thiolase Genes

Thiolase

Gene

Symbol

Comments

ACAA1 acetyl-CoA acyltransferase 1; also called peroxisomal 3-oxoacyl-CoA thiolase; involved in peroxisomalfatty acid -oxidation; located on chromosome 3p22.2 spanning 11 kb composed of 12 exons encoding

a 424 amino acid protein

ACAA2

acetyl-CoA acyltransferase 2; also called mitochondrial 3-oxoacyl-CoA thiolase; catalyzes the terminal

reaction of mitochnodrial fatty acid -oxidation in addition to that catalyzed by HADHB of the MTP;

located on chromosome 18q21.1 encoding a 397 amino acid protein

ACAT1

acetyl-CoA acetyltransferase 1; also called mitochondrial acetoacetyl-CoA thiolase; involved in ketone

body synthesis (see below) in the liver; located on chromosome 11q22.3 spanning 27 kb composed of

12 exons encoding a 427 amino acid protein

ACAT2acetyl-CoA acetyltransferase 2; also called cytosolic acetoacetyl-CoA thiolase; involved in cholesterol

biosynthesisand in the utilization of ketone bodies by the brain; located on chromosome 6q25.3

HADHB

hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit; 3-

ketoacyl-CoA thiolase; -ketothiolase; HADHB encodes the -subunit of mitochondrial trifunctional

protein (MTP); located on chromosome 2p23.3 composed of 16 exons

Each round of -oxidation produces one mole of FADH2, one mole of NADH, and one mole of acetyl-CoA. The

acetyl-CoA, the end product of each round of -oxidation, then enters the TCA cycle, where it is further oxidized to CO2with the concomitant generation of three moles of NADH, one mole of FADH2and one mole of ATP. The NADH and

FADH2generated during the fat oxidation and acetyl-CoA oxidation in the TCA cycle then can enter the respiratory

pathway for the production of ATP via oxidative phosphorylation.

Pathway of mitochondrial -oxidation

The oxidation of fatty acids yields significantly more energy per carbon atom than does the oxidation of

carbohydrates. The net result of the oxidation of one mole of oleic acid (an 18-carbon fatty acid) will be 146 moles of

ATP (2 mole equivalents are used during the activation of the fatty acid), as compared with 114 moles from an

equivalent number of glucose carbon atoms.

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Fat Removal Medical Medical Glucose Reduce Body Fat
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DBP is the primary, if not exclusive enzyme involved in the oxidation of VLCFAs, pristanic acid, and di- and

trihydroxycholestanoic acids. The precise role of LBP in human peroxisomal lipid oxidation is unclear. Human

peroxisomes contain the thiolase acetyl-CoA C-acyltransferase 1 (ACAA1) that catalyzes the terminal step in the

peroxisoaml -oxidation pathway.

The clinical significance of the activity of the acyl-CoA oxidases of peroxisomal -oxidation is related to tissue

specific oxidation processes. In the pancreatic -cell there is little, if any, catalase expressed so that peroxisomal

oxidation of VLCFAs results in an increased release of ROS that can damage the -cell contributing to the progressive

insulin deficiency seen in obesity.

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Microsomal (omega) -Oxidation Reactions

The microsomal (endoplasmic reticulum, ER) pathway of fatty acid -oxidation represents a minor pathway of

overall fatty acid oxidation. However, in certain pathophysiological states, such as diabetes, chronic alcohol

consumption, and starvation, the -oxidation pathway may provide an effective means for the elimination of toxic levels

of free fatty acids. The pathway refers to the fact that fatty acids first undergo a hydroxylation step at the terminal

(omega, ) carbon. Human -hydroxylases are all members of the cytochrome P450 family (CYP) of enzymes. These

enzymes are abundant in the liver and kidneys. Specifically, it is members of the CYP4A and CYP4F families that

preferentially hydroxylate the terminal methyl group of C10C26 length fatty acids. CYP4A11 is the human homolog of

the rat liver CYP4A1 gene whose encoded enzyme was the first -hydroxylase characterized. CYP4A11 utilizes

NADPH and O2to introduce an alcohol to -CH3 of several fatty acids including lauric (12:0), myristic (14:0), palmitic

(16:0), oleic (18:1) and arachidonic acid (20:4). Following addition of the -hydroxyl the fatty acid is a substrate for

alcohol dehydrogenase (ADH) which generates an oxo-fatty acid, followed by generation of the correspondingdicarboxylic acid via the action of aldehyde dehydrogenases (ALDH). Further metabolism then takes place via the -

oxidation pathway in peroxisomes.

Pathway of microsomal (omega) -oxidation as initiated by CYP4A11.

Another human CYP4A subfamily member has been identified and designated CYP4A22. This protein is highly

homologous with CYP4A11 and has been shown to exhibit lauric acid -hydroxylase activity. Expression of CYP4A22

is low in all tissue in which it is found. The CYP4A subfamily is not the only CYP4 family of proteins that have been

found to possess -hydroxylase activity. The CYP4F family enzyme CYP4F3A, which is expressed in leukocytes, isnecessary for the -hydroxylation and subsequent degradation of leukotriene B4(LTB4). LTB4plays an important role

in the modulation of inflammatory processes. The CYP4F3 gene is subject to alternative promoter usage and tissue-

specific gene splicing, which results in two different proteins being produced. These two enzymes are designated

CYP4F3A and CYP4F3B, with the latter enzyme being expressed in the liver. CYP4F3B has higher affinity for

arachidonic acid.

Another CYP4F family member, identified as CYP4F2, has been identified that also has LTB4-hydroxylating

activity. This CYP4F2 protein has a high degree of homology to the CYP4F3B protein and is expressed in the liver and

kidneys. CYP4F2 has been shown to be the major arachidonic acid -hydroxylase in human liver and kidney. Indeed,

the substrate specificity of CYP4F2 for arachidonic acid is much higher than that of CYP4A11 which was originally

described as a signficant arachidonic acid -hydroxylase. The formation of -hydroxylated arachidonic acid (20-

hydroxyeicosatetraenoic acid, 20-HETE) by CYP4A11 plays an important role in the regulation of the cardiovascular

system because 20-HETE is a known vasoconstrictor. Polymorphisms in the CYP4A11 gene are associated with

hypertension in certain population, particular Asian populations. In addition to -hydroxylation of arachidonic acid and

LTB4, CYP4F2 has been shown to be responsible for the -hydroxylation of the phytyl tail of the tocopherols and

tocotrienols (collectively known as vitamin E). Metabolism of vitamin E requires an initial -hydroxylation step followed

by subsequent -oxidation.

Additional members of the CYP4F subfamily have been identified in humans. These genes are designated

CYP4F8, CYP4F11, and CYP4F12. CYP4F8 is present in epithelial linings and catalyzes the (-1)-hydroxylation of

prostaglandin H2(PGH2). CYP4F11 is primarily expressed in liver, but also found in kidney, heart, brain and skeletal

muscle. The primary endogenous substrates for CYP4F11 are long-chain 3-hydroxydicarboxylic acids (3-OHDCAs)

and the enzyme is also very active at hydroxylating various xenobiotics. CYP4F12 is expressed liver, heart,

gastrointestinal and urogenital epithelia and its primary substrates are eicosanoids and xenobiotics.

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Phytanic Acid -Oxidation Reactions

Phytanic acid is a fatty acid present in the tissues of ruminants and in dairy products and is, therefore, an important

dietary component of fatty acid intake. Because phytanic acid is methylated, it cannot act as a substrate for the first

enzyme of the mitochondrial -oxidation pathway (acyl-CoA dehydrogenase). Phytanic acid is first converted to its

CoA-ester and then phytanoyl-CoA serves as a substrate in an -oxidation process. The -oxidation reaction (as well
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as the remainder of the reactions of phytanic acid oxidation) occurs within the peroxisomes and requires a specific -

hydroxylase (specifically phytanoyl-CoA hydroxylase, PhyH), which adds a hydroxyl group to the -carbon of phytanic

acid generating the 19-carbon homologue, pristanic acid. Pristanic acid then serves as a substrate for the remainder

of the normal process of -oxidation. Because the first step in phytanic acid oxidation involves an -oxidation step, the

process is termed -oxidation. For more details on peroxisome function see the Refsum disease page.

Phytanic oxidation pathway

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Regulation of Fatty Acid Metabolism

In order to understand how the synthesis and degradation of fats needs to be exquisitely regulated, one must

consider the energy requirements of the organism as a whole. The blood is the carrier of triglycerides in the form of

VLDLs and chylomicrons, fatty acids bound to albumin, amino acids, lactate, ketone bodies and glucose. The

pancreas is the primary organ involved in sensing the organism's dietary and energetic states by monitoring glucose

concentrations in the blood. Low blood glucose stimulates the secretion of glucagon, whereas, elevated blood glucose

calls for the secretion of insulin.

The metabolism of fat is regulated by two distinct mechanisms. One is short-term regulation, which can come

about through events such as substrate availability, allosteric effectors and/or enzyme modification. The other

mechanism, long-term regulation, is achieved by alteration of the rate of enzyme synthesis and turn-over.

ACC is the rate-limiting (committed) step in fatty acid synthesis. There are two major isoforms of ACC inmammalian tissues. These are identified as ACC1 and ACC2. ACC1 is strictly cytosolic and is enriched in liver,

adipose tissue and lactating mammary tissue. ACC2 was originally discovered in rat heart but is also expressed in

liver and skeletal muscle. ACC2 has an N-terminal extension that contains a mitochondrial targeting motif and is found

associated with CPT-1 allowing for rapid regulation of CPT-1 by the malonyl-CoA produced by ACC. Both isoforms of

ACC are allosterically activated by citrate and inhibited by palmitoyl-CoA and other short- and long-chain fatty acyl-

CoAs. Citrate triggers the polymerization of ACC1 which leads to significant increases in its activity. Although ACC2

does not undergo significant polymerization (presumably due to its mitochondrial association) it is allosterically

activated by citrate. Glutamate and other dicarboxylic acids can also allosterically activate both ACC isoforms.

ACC activity can also be affected by phosphorylation. Both ACC1 and ACC2 contain at least eight sites that

undergo phosphorylation. The sites of phosphorylation in ACC2 have not been as extensively studied as those in

ACC1. Phosphorylation of ACC1 at three serine residues (S79, S1200, and S1215) byAMPKleads to inhibition of

the enzyme. Glucagon-stimulated increases in cAMP and subsequently to increased PKA activity also lead to

phosphorylation of ACC. ACC2 is a better substrate for PKA than is ACC1. The activating effects of insulin on ACCare complex and not completely resolved. It is known that insulin leads to the dephosphorylation of the serines in ACC1

that are AMPK targets in the heart enzyme. This insulin-mediated effect has not been observed in hepatocytes or

adipose tissues cells. At least a portion of the activating effects of insulin are related to changes in cAMP levels. Early

evidence has shown that phosphorylation and activation of ACC occurs via the action of an insulin-activated kinase.

However, contradicting evidence indicates that although there is insulin-mediated phosphorylation of ACC this does

not result in activation of the enzyme. Activation of -adrenergic receptors in liver and skeletal muscle cells inhibits

ACC activity as a result of phosphorylation by an as yet undetermined kinase.

Insulin, a product of the well-fed state, stimulates ACC and FAS synthesis, whereas starvation leads to a decrease

in the synthesis of these enzymes. Adipose tissue levels of lipoprotein lipase also are increased by insulin and

decreased by starvation. However, the effects of insulin and starvation on lipoprotein lipase in the heart are just the

inverse of those in adipose tissue. This sensitivity allows the heart to absorb any available fatty acids in the blood in

order to oxidize them for energy production. Starvation also leads to increases in the levels of cardiac enzymes of fatty

acid oxidation, and to decreases in FAS and related enzymes of synthesis.Adipose tissue contains hormone-sensitive lipase (HSL), which is activated by PKA-dependent phosphorylation;

this activation increases the release of fatty acids into the blood. This in turn leads to the increased oxidation of fatty

acids in other tissues such as muscle and liver. In the liver, the net result (due to increased acetyl-CoA levels) is the

production of ketone bodies (see below). This would occur under conditions in which the carbohydrate stores and

gluconeogenic precursors available in the liver are not sufficient to allow increased glucose production. The increased

levels of fatty acid that become available in response to glucagon or epinephrine are assured of being completely

oxidized, because PKA also phosphorylates ACC; the synthesis of fatty acid is thereby inhibited.

The activity of HSL is also affected via phosphorylation by AMPK. In this case the phosphorylation inhibits the

enzyme. Inhibition of HSL by AMPK may seem paradoxical since the release of fatty acids stored in triglycerides would

seem necessary to promote the production of ATP via fatty acid oxidation and the major function of AMPK is to shift

cells to ATP production from ATP consumption. This paradigm can be explained if one considers that if the fatty acids

that are released from triglycerides are not consumed they will be recycled back into triglycerides at the expense of

ATP consumption. Thus, it has been proposed that inhibition of HSL by AMPK mediated-phosphorylation is amechanism to ensure that the rate of fatty acid release does not exceed the rate at which they are utilized either by

export or oxidation.

Insulin has the opposite effect to glucagon and epinephrine: it increases the synthesis of triacylglycerols (and

glycogen). One of the many effects of insulin is to lower cAMP levels, which leads to increased dephosphorylation

through the enhanced activity of protein phosphatases such as PP-1. With respect to fatty acid metabolism, this yields
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dephosphorylated and inactive hormone-sensitive lipase. Insulin also stimulates certain phosphorylation events. This

occurs through activation of several cAMP-independent kinases.

Fat metabolism can also be regulated by malonyl-CoA-mediated inhibition of CPT I. Such regulation serves to

prevent de novosynthesized fatty acids from entering the mitochondria and being oxidized.

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The Glucose-Fatty Acid Cycle

The glucose-fatty acid cycle describes interrelationships of glucose and fatty acid oxidation as defined by fuel flux

and fuel selection by various organs. This cycle is not a metabolic cycle such as can be defined by the TCA cycleas anexample, but defines the dynamic interactions between these two major energy substrate pools. The glucose-fatty acid

cycle was first proposed by Philip Randle and co-workers in 1963 and is, therefore, sometimes referred to as the

Randle cycle or Randle hypothesis. The cycle describes how nutrients in the diet can fine-tune metabolic processes on

top of the more coarse control exerted by various peptide and steroid hormones. The underlying theme of the glucose-

fatty acid cycle is that the utilization of one nutrient (e.g. glucose) directly inhibits the use of the other (in this case fatty

acids) without hormonal mediation. The general interrelationships between glucose and fatty acid utilization in skeletal

muscle and adipose tissue that constitutes the glucose-fatty acid cycle are diagrammed in the Figure below.

The glucose-fatty acid cycle represents the interactions between glucose uptake and metabolism and the

consequent inhibition of fatty acid oxidation and the effects of fatty acid oxidation on the inhibition of glucose

utilization. The reciprocal regulation is most prevalent in skeletal muscle and adipose tissue. When glucose levels

are high it is taken into cells via the GLUT4 transporter and phosphorylated by hexokinase. The reactions of

glycolysis drive the carbon atoms to pyruvate where they are oxidized to acetyl-CoA. The fate of the acetyl-CoA iscomplete oxidation in the TCA cycleor return to the cytosol via citrate for conversion back to acetyl-CoA via ATP-

citrate lyase (ACLY) and then into into malonyl-CoA and subsequent long-chain fatty acid (LCFA) synthesis. The

synthesis of malonyl-CoA is catalyzed by acetyl-CoA carboxylase (ACC) and once produced will inhibit the import of

long-chain fatty acyl-CoAs (LCFacyl-CoA) into the mitochondria via inhibition of carnitine palmitoyltransferase 1

(CPT-1). This effectively blocks the oxidation of fatty acids leading to increased triacylglyceride synthesis (TAG). The

equilibrium between malonyl-CoA synthesis and breakdown back to acetyl-CoA is determined by the regulation of

ACC and malonyl-CoA decarboxylase (MCD). As long as there is sufficient capacity to divert glucose carbons to

TCA cycle oxidation and fatty acid synthesis there will be limited acetyl-CoA mediated inhibition of the pyruvate

dehydrogenase complex (PDHc). On the other hand, when fatty acid levels are high they enter the cell via one of

several fatty acid transporter complexes [fatty acid translocase (FAT)/CD36 is shown since this transporter has a

preference for LCFAs], and are then transported into the mitochondria to be oxidized. The large increase in fatty acid

oxidation subsequently inhibits the utilization of glucose. This is the result of increased cytosolic citrate production

from acetyl-CoA and the inhibition of phosphofructokinase-1 (PFK1). The increased acetyl-CoA derived from fat

oxidation will in turn further inhibit glucose utilization via activation of PDH kinases (PDKs) that will phosphorylate and

inhibit the PDHc. Although not shown, PDKs are also activated by increased mitochondrial NADH/NAD + ratios in

response to increased fatty acid -oxidation. Under conditions where fat oxidation is favored ACC will be inhibited

and MCD will be activated ensuring that LCFA that enter the cell will be able to be transported into the mitochondria.

PS is pyruvate symporter responsible for mitochondrial uptake of pyruvate. TCAT is tricarboxylic acid transporter.

How do the dynamics of the glucose-fatty acid cycle play out under various physiological conditions and changing

fuel substrate pools? In the fasted state it is imperative that glucose be spared so that the brain can have adequate

access to this vital fuel. Under these conditions, hormonal signals from the pancreas, in the form of glucagon, stimulate

adipose tissue lipolysis releasing free fatty acids (FFAs) to the blood for use as a fuel by other peripheral tissues.

When the released FFAs enter the liver they oxidized and also serve as substrates for ketogenesis. The oxidation of

fatty acids inhibits glucose oxidation as outlined in the above figure. In addition to sparing glucose for the brain, fatty

acid oxidation also preserves pyruvate and lactate which are important gluconeogenesis substrates. The effects of

fatty acids on glucose utilization can also be observed in the well fed state after a high fat meal and during periods ofexercise.

As outlined in the above Figure, the inhibition of glucose utilization by fatty acid oxidation is mediated by short-

term effects on several steps of overall glycolysis that include glucose uptake, glucose phosphorylation and pyruvate

oxidation. During fatty acid oxidation the resultant acetyl-CoA allosterically activates PDKs that phosphorylate and

inhibit the PDHc. PDKs are also activated by increasing levels of NADH that will be the result of increased fatty acid

oxidation. Thus, two products of fat oxidation result in inhibition of the PDHc. In addition, excess acetyl-CoA is

transported to the cytosol either as citrate (as diagrammed) or as acetyl-carnitine. Mitochondrial acetyl-carnitine is

formed through the action of carnitine acetyltransferase (CAT). Acetyl-carnitine is transported out of the the

mitochondria via the action of carnitine-acylcarnitine translocase (CACT). Once in the cytosol acetyl-carnitine is

converted to acetyl-CoA via the action of cytosolic CAT. In the cytosol, citrate serves as an allosteric inhibitor of PFK1

thus limiting entry of glucose into glycolysis. The increase in glucose-6-phosphate that results from inhibition of PFK1

leads to feed-back inhibition of hexokinase which in turn limits glucose uptake via GLUT4. Additional mechanisms of

fatty acid metabolism that lead to interference in glucose uptake and utilization are the result of impaired insulinreceptor signaling. These latter processes are discussed in detail in the Insulin Functionpage.

Mechanisms by which glucose utilization inhibits fatty acid oxidation are tissue specific due primarily to the

differences in Km of hepatic glucokinase and skeletal muscle and adipose tissue hexokinase. In addition, hepatic

CPT-1 is approximately 100-fold less sensitive to inhibition by malonyl-CoA than are the skeletal muscle and cardiac

isoforms. When glucose is oxidized in glycolysis the resultant pyruvate enters the mitochondria via the pyruvate
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symporter. Increasing mitochondrial pyruvate inhibits the PDKs allowing for rapid decarboxylation of pyruvate by the

PDHc ensuring continued entry of glucose into the glycolytic stream. Some of the acetyl-CoA derived from pyruvate

oxidation will be diverted from the TCA cycle as citrate and transported to the cytosol by the tricarboxylic acid

transporter (TCAT). The citrate is converted to acetyl-CoA and oxaloacetate by ATP-citrate lyase (ACLY) and can now

serve as a substrate for ACC. The resultant malonyl-CoA will inhibit CPT-1 thus, restricting mitochondrial uptake and

oxidation of fatty acyl-CoAs. The inhibition of fatty acid oxidation in the liver re-routes LCFAs into triglycerides (TAGs).

Long term effects of excess glucose are reflected in hepatic steatosis resulting from the diversion of fats into TAGs

instead of being oxidized.

In addition to being regulated by intermediates of glucose and fat oxidation, several enzymes in these two

pathways are regulated at the level of post-translational modification and/or gene expression. Most of these regulatory

schemes have been covered in the above sections.

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Clinical Significance of Fatty Acids

The majority of clinical problems related to fatty acid metabolism are associated with processes of oxidation.

These disorders fall into four main groups:

1. Deficiencies in Carnitine: Deficiencies in carnitine lead to an inability to transport fatty acids into the

mitochondria for oxidation. This can occur in newborns and particularly in pre-term infants. Carnitine deficiencies also

are found in patients undergoing hemodialysis or exhibiting organic aciduria. Carnitine deficiencies may manifest

systemic symptomology or may be limited to only muscles. Symptoms can range from mild occasional muscle

cramping to severe weakness or even death. Treatment is by oral carnitine administration.

2. Carnitine palmitoyltransferase deficiencies:Deficiencies in CPT-1 are relatively rare and affect primarily

the liver and lead to reduced fatty acid oxidation and ketogenesis. The most common symptom associated with CPT-1

deficiency is hypoketotic hypoglycemia. There is also an elevation in blood levels of carnitine. The liver involvement

results in hepatomegaly and in muscles results in weakness. CPT-2 deficiencies can be classified into three main

forms. The adult form affects primarily the skeletal muscles and is called the adult myopathic form. This form of the

disease causes muscle pain and fatigue and myoglobinuria following exercise. The severe infantile multisystem form

manifest in the first 624 months of life with most afflicted infants demonstrating significant involvement before 1 year.

The primary symptom of this form of CPT-2 deficiency is hypoketotic hypoglycemia. Symptoms will progress to severe

hepatomegaly and cardiomyopathy. Often times death from CPT-2 deficiency may be mis-diagnosed as sudden infant

death syndrome, SIDS. The rarest form of CPT-2 deficiency is referred to as the neonatal lethal form. Symptoms of this

form appear within hours to 4 days after birth and include respiratory failure, hepatomegaly, seizures, hypoglycemia,

and cardiomegaly. The cardiomegaly will lead to fatal arrhythmias. Carnitine acyltransferases may also be inhibited by

sulfonylurea drugs such as tolbutamide and glyburide.

3. Deficiencies in Acyl-CoA Dehydrogenases: A group of inherited diseases that impair -oxidation result

from deficiencies in acyl-CoA dehydrogenases. The enzymes affected may belong to one of three categories:

long-chain acyl-CoA dehydrogenase (LCAD)

medium-chain acyl-CoA dehydrogenase (MCAD)

short-chain acyl-CoA dehydrogenase (SCAD)

MCAD deficiencyis the most common form of acyl-CoA dehydrogenase deficiency. In the first years of life this

deficiency will become apparent following a prolonged fasting period. Symptoms include vomiting, lethargy and

frequently coma. Excessive urinary excretion of medium-chain dicarboxylic acids as well as their glycine and carnitine

esters is diagnostic of this condition. In the case of this enzyme deficiency taking care to avoid prolonged fasting is

sufficient to prevent clinical problems.

4. Refsum Disease: Refsum disease is a rare inherited disorder in which patients harbor a defect in theperoxisomal -oxidizing enzyme, phytanoyl-CoA hydroxylase (PhyH). Although mutations in PhyH are the primary

cause of Refsum disease, the syndrome can also result from defects in the peroxisomal protein (PEX7) responsible

for the import of PhyH into the peroxisome. Patients accumulate large quantities of phytanic acid in their tissues and

serum. This leads to severe symptoms, including cerebellar ataxia, retinitis pigmentosa, nerve deafness and

peripheral neuropathy. As expected, the restriction of dairy products and ruminant meat from the diet can ameliorate

the symptoms of this disease. It should be noted that accumulation of phytanic acid is not solely the result of defects in

PhyH. Phytanic acid accumulation is also seen when there are inherited defects in peroxisome function leading to

Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease. In addition, rhizomelic

chondrodysplasia punctata, type 1(RCDP1) results in phytanic acid accumulation. Refsum disease due to deficiency

in PhyH is properly referred to as classical Refsum diseaseto distinguish it from infantile Refsum due to peroxisome

dysfunction.

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Ketogenesis

During high rates of fatty acid oxidation, primarily in the liver, large amounts of acetyl-CoA are generated. These

exceed the capacity of the TCA cycle, and one result is the synthesis of ketone bodies. The synthesis of the ketone

bodies (ketogenesis) occurs in the mitochondria allowing this process to be intimately coupled to rate of hepatic fatty
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acid oxidation. Conversely, the utilization of the ketones (ketolysis) occurs in the cytosol. The ketone bodies are

acetoacetate, -hydroxybutyrate, and acetone.

The formation of acetoacetyl-CoA occurs by condensation of two moles of acetyl-CoA. This reaction is essentially

a reversal of the thiolase (HADHB or ACAA2) catalyzed reaction of -oxidation but is in fact catalyzed by the

mitochondrial enzyme acetoacetyl-CoA thiolase (encoded by the ACAT1 gene). Acetoacetyl-CoA and an additional

acetyl-CoA are converted to -hydroxy--methylglutaryl-CoA (HMG-CoA) by mitochondrial HMG-CoA synthase

(encoded by the HMGCS2 gene), an enzyme found in large amounts only in the liver. HMG-CoA in the mitochondria is

converted to acetoacetate by the action of HMG-CoA lyase. Acetoacetate can undergo spontaneous decarboxylation

to acetone, or be enzymatically converted to -hydroxybutyrate through the action of -hydroxybutyrate dehydrogenase.

The ketone bodies freely diffuse out of the mitochondria and hepatocytes and enter the circulation where they can be

taken up by non-hepatic tissues such as the brain, heart, and skeletal muscle.

Synthesis of the ketones

When the level of glycogen in the liver is high the production of -hydroxybutyrate increases. When carbohydrate

utilization is low or deficient, the level of oxaloacetate will also be low, resulting in a reduced flux through the TCA cycle.

This in turn leads to increased release of ketone bodies from the liver for use as fuel by other tissues. In early stages of

starvation, when the last remnants of fat are oxidized, heart and skeletal muscle will consume primarily ketone bodies

to preserve glucose for use by the brain. Acetoacetate and -hydroxybutyrate, in particular, also serve as major

substrates for the biosynthesis of neonatal cerebral lipids.

Ketone bodies are utilized by extrahepatic tissues via a series of cytosolic reactions that are essentially a reversal

of ketone body synthesis. The initial steps involve the conversion of -hydroxybutyrate to acetoacetate and of

acetoacetate to acetoacetyl-CoA. The first step involves the reversal of the -hydroxybutyrate dehydrogenase reaction.

It is important to appreciate that under conditions where tissues are utilizing ketones for energy production their

NAD+/NADH ratios are going to be relatively high, thus driving the -hydroxybutyrate dehydrogenase catalyzed

reaction in the direction of acetoacetate synthesis. The second reaction of ketolysis involves the action (shown below)

of succinyl-CoA:3-oxoacid-CoA transferase (SCOT), also called 3-oxoacid-CoA transferase 1 (OXCT1). The latter

enzyme is present at high levels in most tissues except the liver. Importantly, very low level of SCOT expression in the

liver allows the liver to produce ketone bodies but not to utilize them. This ensures that extrahepatic tissues have

access to ketone bodies as a fuel source during prolonged fasting and starvation.

Utilization of the ketones

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Regulation of KetogenesisThe fate of the products of fatty acid metabolism is determined by an individual's dietary and physiological status.

The overall rate of hepatic ketogenesis may by affected by several factors:

1.Control in the release of free fatty acids from adipose tissue directly affects the level of ketogenesis in the

liver. This is, of course, substrate-level regulation. Fatty acid release from adipose tissue is controlled via the

activity of hormone-sensitive lipase (HSL). When glucose levels fall, pancreatic glucagon secretion increases

resulting in phosphorylation of adipose tissue HSL, thus resulting in increased hepatic ketogenesis due to

increased substrate (free fatty acids) delivery from adipose tissue. Conversely, insulin, released in the well-fed

state, inhibits ketogenesis via the triggering of dephosphorylation and inactivation of adipose tissue HSL.

2.Once fats enter the liver, they have two distinct fates. They may be activated to acyl-CoAs and oxidized, or

esterified to glycerol in the production of triacylglycerols. If the liver has sufficient supplies of glycerol-3-

phosphate, most of the fats will be turned to the production of triacylglycerols.

3.The acetyl-CoA generated by the oxidation of fats can be completely oxidized in the TCA cycle or it can be

diverted into lipid biosynthesis. If the hepatic demand for ATP is high the fate of acetyl-CoA is likely to be further

oxidation to CO2. This is especially true under conditions of hepatic stimulation by glucagon which results in

increased gluconeogenesis and the energy for this process is derived primarily from the oxidation of fatty acids

supplied from adipose tissue.

4. In addition, glucagon results in phosphorylation and inhibition of acetyl-CoA carboxylase (ACC), the rate

limiting enzyme of de novofatty acid synthesis. Conversely, under conditions of insulin release, hepatic ACC is

activated and the excess acetyl-CoA will be converted into malonyl-CoA and then free fatty acids. The increased

malonyl-CoA results in inhibition of fatty acid transport into the mitochondria resulting in reduced fat oxidation

and reduced production of excess acetyl-CoA.

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Clinical Significance of Ketogenesis

The production of ketone bodies occurs at a relatively low rate during normal feeding and under conditions of

normal physiological status. Normal physiological responses to carbohydrate shortages cause the liver to increase the

production of ketone bodies from the acetyl-CoA generated from fatty acid oxidation. This allows the heart and skeletal
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muscles primarily to use ketone bodies for energy, thereby preserving the limited glucose for use by the brain.

The most significant disruption in the level of ketosis, leading to profound clinical manifestations, occurs in

untreated insulin-dependent diabetes mellitus. This physiological state, diabetic ketoacidosis(DKA) results from a

reduced supply of glucose (due to a significant decline in circulating insulin) and a concomitant increase in fatty acid

oxidation (due to a concomitant increase in circulating glucagon). The increased production of acetyl-CoA leads to

ketone body production that exceeds the ability of peripheral tissues to oxidize them. Ketone bodies are relatively

strong acids (pKa around 3.5), and their increase lowers the pH of the blood. This acidification of the blood is

dangerous chiefly because it impairs the ability of hemoglobin to bind oxygen.

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Michael W King, PhD | 19962013 themedicalbiochemistrypage.org, LLC | info @ themedicalbiochemistrypage.org

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