Catabolism of fats in human organismjulivan/MF rudens semestras/Basis of... · • Metabolism of fatty acids (anabolism and catabolism) begins with activation – conjugation to coenzyme

Catabolism of fats in human organism

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

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.

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

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.

Mechanism of activation of

tissue lipolysis by hormones

Fate of FFA in tissue

• Breakdown • Accumulation as the synthesis of TAG

takes place in adipocytes.

Principles of the breakdown of FFA

In m

itoch

ondr

ia In mitochondria

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.

Transfer of activated fatty acid into mitochondria

CPTI and II iscarnitine palmityltransferase

Cytosol

Matrix of mitochondria

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.

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

3-hydroxyacyl-CoAdehydrogenase

NAD+ NADH + H+

3.

+

β-ketoacyl-CoAthiolase

Continues until acyl unitis decomposed into acetyl-CoA

4.

Energy yield in FA oxidation

Oxidationof unsaturated

FA

Oxidation of odd-number of C atoms

containing FA

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).

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

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.

Consumption of ketone bodies in mitochondria(from Krebs cycle)

(toKrebs cycle)

2 Acetyl-CoA

Thiolase

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.

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.

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)

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.

Structure ofFA synthase

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.

Dependance of fatty acid oxidation from glucose oxidation

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)

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.

Desaturation of fatty acids