catabolism of fats in human organismjulivan/mf rudens semestras/basis of... · • metabolism of...
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Catabolism of fats in human organism
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What are fats and fatty acids
A molecule of a fat(TAG – triacylglycerol)
• Fats are neutral lipids: a greasy substances whose molecules are esters of glycerol and long-chain carboxylic acids.
• Fatty acids are long-chain carboxylic acids released from fats after their hydrolysis A molecule of
fatty acid with 14 C atoms –myristic acid
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Sources of fatty acids in humans
• Dietary fats. Products of fat digestion delivered with blood lipoproteins (chylomicrons) donate free fatty acids.
• Fats stored in adipose tissue.Breakdown of fat deposits in adipose tissue is considered as tissue lipolysis or endogenous lipolysis.
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Formation of chylomicronChylomicron is a type of blood lipoproteins released from enterocytes
Cylomicron is broken down by lipoprotein lipase releasing free fatty acids and chylomicron remnant contatining less TAG
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Characteristics of tissue lypolysis
• It occurs in response to stress or hunger hormones, such as epinephrine or glucagon.
• It is carried out by 3 enzymes specific in regard to substrate: TAG lipase, DAG lipase, and MAG lipase.
• TAG lipase is a regulatory enzyme controlled by reversible covalen modification (phosphorylation).
• Free fatty acids (FFA) and glycerol are the end products of tissue lipolysis.
• FFA released from adipose tissue are transferred by albumin in the blood.
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Mechanism of activation of
tissue lipolysis by hormones
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Fate of FFA in tissue
• Breakdown • Accumulation as the synthesis of TAG
takes place in adipocytes.
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Principles of the breakdown of FFA
In m
itoch
ondr
ia In mitochondria
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Fatty acid activation
• Free fatty acids are inert.• Metabolism of fatty acids (anabolism and
catabolism) begins with activation – conjugation to coenzyme A.
• Activation is carried out by Acyl-CoA synthetaselocated in the outer membrane of mitochondria.Fatty acid + CoA-SH+ATP→Acyl-S~CoA + +AMP + 2Pi
• Acyl-S~CoA is activated fatty acid which undergoes further metabolism.
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Transfer of activated fatty acid into mitochondria
CPTI and II iscarnitine palmityltransferase
Cytosol
Matrix of mitochondria
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Characteristics of β-oxidation
• β-oxidation is a way of acyl-unit [CH3-(CH2)n-C=O] breakdown, when covalent bond is broken after the third or β C atom in the unit.
• The enzyme system of β-oxidation includes 4 enzymes. The enzymes are specific in regard to the number of C atoms in the unit (for long chain of acyl; for middle-long- and short-chain).
• In a single round of β-oxidation, acetyl-unit is released as acetyl-CoA.
• Number of acetyl-CoA molecules released in all rounds of β-oxidation is twice less than the number of C atoms in fatty acidsubjected to breakdown.
• Number of rounds of β-oxidations required form decomposition of fatty acid, is equal (n-1), where n is the number of acetyl-CoA molecules.
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Stages of beta-oxidationCH3-CH2-CH2-CH2-CH2-CO~S-CoA
3(β) 2(α) 1
Stage 1 – oxidationof 2nd and 3rd C atom
CH3-CH2-CH2-CH CH-CO~S-CoA
CH3-CH2-CH2-CH CH2-CO~S-CoA
OH
Stage 2 - Adding ofwater moleculeto double
CH3-CH2-CH2-C CH2-CO~S-CoA
O
Stage 3 – oxidation of 3rd C atom
CH3-CH2-CH2-C CH2-CO~S-CoA
O Stage 4 – Breakdown of bond between 2nd and 3rd C atoms
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3-hydroxyacyl-CoAdehydrogenase
NAD+ NADH + H+
3.
+
β-ketoacyl-CoAthiolase
Continues until acyl unitis decomposed into acetyl-CoA
4.
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Energy yield in FA oxidation
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Oxidationof unsaturated
FA
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Oxidation of odd-number of C atoms
containing FA
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Synthesis of ketone bodies
• Oxidation of fatty acids produce big amounts of acetyl-CoA which has to be broken down in mitochondria.
• In the liver cells, activity of Krebs cycle can be diminished because of oxaloacetate withdrawal for gluconeogenesis.
• Excessive amounts of acetyl-CoA are converted into ketone bodies.
• In blood of healthy individuals, concentration of ketone bodies is up to 2 mg/100 ml of plasma.
• Acetoacetate and 3-hydroxybutyrate are the principal ketone bodies in healthy individuals.
• Acetone is a spontaneous product of acetoacetate decarboxylation occuring under high concentrations of acetoacetate (in starvation and DM).
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Synthesis of ketone bodies In mitochondria of the liver cells
Acetoacetyl-CoA
3-hydroxy-3-methylglutaryl-CoA (HMG-CoA)
Acetoacetate Acetyl-CoA
3NADH+H+
NAD+
Common with synthesisof cholesterol
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Consumption of ketone bodies
• Brain and cells of the heart are the principal consumers of ketone bodies from blood.
• Ketone bodies (acetoacetate and 3-hydroxybutyrate) can be broken down in those cells releasing energy.
• High amounts of ketone bodies are produced under starvation.
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Consumption of ketone bodies in mitochondria(from Krebs cycle)
(toKrebs cycle)
2 Acetyl-CoA
Thiolase
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Characteristics of fatty acid (FA) synthesis
• FA synthesis occurs under insufficient dietary intake of lipids.• FA which cannot be synthesized in humans are referred as
essential fatty acids. There are two essential fatty acids for humans: linoic acid and linolenic acid. Both they contain double bond located further than C10.
• Fatty acid chains are constructed by the addition of two-carbon units derived from acetyl-CoA. Acetyl-CoA from carbohydrates is a preferable substrate for this synthesis.
• The acetate units are activated by formation of malonyl-CoA (ATP is required) which is a principal donor of two C atoms.
• FA synthesis occurs in smooth ER of the liver cells. It is carried out by multienzyme complex FA synthase, which produces palmitic (16 C) acid as a final product.
• Palmitic acid can be converted into both a FA with longer chain and an unsaturated FA.
• Consumes NADPH formed in the PPP.
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Transportation of acetyl-unit out of mitochondria
• Acetyl-CoA is being formed only in mitochondria.
• A shuttle system is required for acetyl-unit transferring.
• The citrate-malate-pyruvate shuttle is active in mitochondria of the liver cells.
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Stages of fatty acid synthesis
• Activation of acetyl-unit producing malonyl-CoA.• Initiation by binding of acetyl- and malonyl-group
to acyl-carrier-protein of FA synthase.• Formation of butiryl-unit with 4 C atoms in FA
synthase.• Elongation by binding of acetyl-unit from
malonyl-ACP to growing fatty acid chain.• Release of palmitic acid (saturated FA with 16 C
atoms in the chain)
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Formation of malonyl- CoA• Occurs in the cytosol of
hepatocyte.• Acetyl-CoA carboxylase is an
allosteric enzyme containing biotin as a coenzymes.
• Citrate is an allosteric activator of acetyl-CoA carboxylase.
• The enzyme is subjected to feed-back inhibition by palmitic acid the end product of FA synthesis
• Acetyl-CoA carboxylase is also regulated by reversible phosphorylation. Insulin activates the enzyme. Glucagon inhibits it.
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Structure ofFA synthase
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FA synthesis andFA oxidation are reciprocally regulated.The central regulatorypoint is acetyl-CoA carboxylase, whoseproduct malonyl-CoA isinhibitor of CPTI. Becauseof this inhibition, the FA oxidation does not occurwhen FA synthesis continues.Homones activating formation of cAMP, promote the phosphorylation, thereby decreasing its activity.
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Dependance of fatty acid oxidation from glucose oxidation
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Synthesis of FA containing more than 16 C atoms
• From palmityl-CoA, the chain elongation occurs in the smooth ER by adding 2 C atom containing unit from malonyl-CoA.
• NADPH is a reductant under eleongation.• A most common product of elongation is
saturated fatty acid containing 18 C atoms (stearic acid)
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Synthesis of unsaturated fatty acids
• Unsaturated fatty acids are being formed from saturated ones by a complex ezyme known as desaturatse in ER of liver cells.
• Desaturase requires molecular oxygen, NADH and cytochrome b5. Thus, desaturation is related to the ETC.
• Desaturase can place double bonds only between 10 C and carboxyl group, e.g. as in palmitoleic acid and oleic acid.
• Unsaturated fatty acids with double bond located after 10 C are considered as essential ones.
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Desaturation of fatty acids