Lipid metabolism

metabolism of lipids

1. LIPID METABOLISM DEVIPRIYA P V M PHARM

2. CONTENTS β-Oxidation of saturated fatty acid ( Palmitic acid) Formation and utilization of ketone bodies Ketoacidosis De novo synthesis of fatty acids ( Palmitic acid) Biological significance of cholesterol Conversion of cholesterol into bile acids, steroid hormone and vitamin D Disorders of lipid metabolism: Hypercholesterolemia, atherosclerosis, fatty liver and obesity.

3. β -oxidation of saturated fatty acids The fatty acids in the body are mostly oxidized by β -oxidation. β -Oxidation is the oxidation of fatty acids on the β -carbon atom . This results in the sequential removal of a two carbon fragment , acetyl CoA . The β -oxidation of fatty acids involves three stages: Activation of fatty acids occurring in the cytosol ; Transport of fatty acids into mitochondria; β -Oxidation proper in the mitochondrial matrix.

4. Fatty acid activation: Fatty acids are activated to acyl CoA by thiokinases or acyl CoA synthetases . The reaction occurs in 2 steps and requires ATP, coenzyme A and Mg2+. Fatty acid reacts with ATP to form acyladenylate which then combines with coenzyme A to produce acyl CoA . Transport of fatty acids into mitochondria: Carnitine carrier system is used for the transport of activated fatty acids from cytosol to mitochondria. This occurs in 4 steps: Acyl group of acyl CoA is transferred to carnitine catalysed by carnitine acyl transferase I The acyl-carnitine is transported across the membrane to mitochondrial matrix by a specific carrier protein. Carnitine acyl transferase ll converts acyl-carnitine to acyl CoA . The carnitine released returns to cytosol for reuse.

5. β -Oxidation proper: (4 reactions) (1)Oxidation : Acyl CoA undergoes dehydrogenation by an FAD-dependent flavoenzyme , acyl CoA dehydrogenase. A double bond is formed between α and β carbons. (2)Hydration : Enoyl CoA hydratase brings about the hydration of the double bond to form β - hydroxyacyl CoA . (3)Oxidation : β - Hydroxyacyl CoA dehydrogenase catalyses the second oxidation and generates NADH. The product formed is β – ketoacyl CoA . (4)Cleavage : Liberation of a 2 carbon fragment, acetyl CoA from acyl CoA . This occurs by a thiolytic cleavage catalysed by β - ketoacyl CoA thiolase

6. Ketogenesis The synthesis of ketone bodies occurs in the Iiver . The enzymes for ketone body synthesis are located in the mitochondrial matrix. Acetyl CoA , pyruvate or some amino acids , is the precursor for ketone bodies. Reactions in Ketogenesis : (1)Two moles of acetyl CoA condense to form acetoacetyl CoA by the action of thiolase . (2) Acetoacetyl CoA combines with another molecule of acetyl CoA in the presence of HMG CoA synthase to produce β – hydroxy β -methyl glutaryl CoA (HMG CoA ).

7. ( 3) HMG CoA lyase cleaves HMG CoA to produce acetoacetate and acetyl CoA . (4) Acetoacetate can undergo spontaneous decarboxylation to form acetone. (5) Acetoacetate can be reduced by a dehydrogenease to β - hydroxybutyrate .

8. Utilization of ketone bodies The ketone bodies (water-soluble) are easily transported from the liver to various tissue. The two ketone bodies- acetoacetate and β - hydroxy butyrate are important sources of energy for skeletal muscle, cardiac muscle/ renal cortex etc. Tissues which lack mitochondria cannot utilize ketone bodies. The production and utilization of ketone bodies is more significant when there is a short supply of glucose to tissues, as in starvation, and diabetes mellitus . During prolonged starvation , ketone bodies are the major fuel source for the brain and other parts of CNS. The ketone bodies can meet 50-70% of the brain's energy needs.

9. Reactions of ketone bodies: β - Hydroxybrutyrate is converted to acetoacetate Acetoacetate is activated to aceto acetyl CoA by the enzyme thiophorase Thiophorase is absent in liver, hence ketone bodies are not utilized by the liver. Thiolase cleaves aceto acetyl CoA to 2 moles of acetyl CoA

10. Ketoacidosis Both acetoacetate and β - hydroxybutyrate are strong acids . Increase in their concentration in blood would cause acidosis. ketone bodies in the blood dissociate and release H+ ions which lower the pH. Further, plasma volume in the body is reduced due to dehydration caused by the excretion of glucose and ketone bodies. Diabetic ketoacidosis may result in coma, and even death, if not treated. Rapid treatment of diabetic ketoacidosis is required to correct the metabolic abnormalities and the associated water and electrolyte imbalance. Insulin administration is necessary to stimulate uptake of glucose by tissues and inhibition of ketogenesis

11. De novo synthesis of fatty acids De novo (new) synthesis of fatty acids occurs predominantly in liver, kidney, adipose tissue and lactating mammary glands. The enzymes required are present in the cytosomal fraction of the cell. 3 stages of fatty acid synthesis: Production of acetyl CoA and NADPH Conversion of acetyl CoA to malonyl CoA Reactions of fatty acid synthase complex.

12. Production of acetyl CoA and NADPH: Fatty acid synthesis requires Acetyl CoA and NADPH . Acetyl CoA is produced in the mitochondria by the oxidation of pyruvate and fatty acids, degradation of carbon skeleton of certain amino acids, and from ketone bodies. As acetyl CoA is not permeable to mitochondria, it is converted to citrate. Citrate is freely transported to cytosol where it is cleaved by citrate lyase to liberate acetyl CoA and oxaloacetate . Oxaloacetate in the cytosol is converted to malate . Malic enzyme converts malate to pyruvate . NADPH and CO 2 are generated in this reaction, which are utilized for fatty acid synthesis

13. Formation of malonyl CoA : Acetyl CoA is carboxylated to malonyl CoA by the enzyme acetyl CoA carboxylase . Reactions of fatty acid synthase complex: The remaining reactions of fatty acid synthesis are catalysed by a fatty acid synthase (FAS) complex . The 2 carbon fragment of acetyl CoA is transferred to ACP( acyl carrier protein) of fatty acid synthase . The acetyl unit is then transferred from ACP to cysteine residue of the enzyme. Thus ACP site falls vacant. The enzyme malonyl CoA -ACP transacylase transfers malonate from malonyl CoA to bind to ACP. The acetyl unit attached to cysteine is transferred to malonyl group.The malonyl moiety loses CO 2 which was added by acetyl CoA carboxylase . This reaction is catalyzed by β - ketoacyl ACP synthase

14. β - Ketoacyl ACP reductase reduces ketoacyl group to hydroxyacyl group. β – Hydroxyacyl ACP undergoes dehydration. A molecule of water is eliminated and a double bond is introduced between α and β carbons. A second NADPH-dependent reduction, catalysed by enoyl -ACP reductase , occurs to produce acyl -ACP. The carbon chain attached to ACP is transferred to cysteine residue. The enzyme palmitoyl thioesterase separates palmitate from fatty acid synthase .

15. Biological significance of cholesterol Cholesterol is found exclusively in animals, hence it is often called as animal sterol. Cholesterol is amphipathic in nature(possess both hydrophilic and hydrophobic regions). It is a structural component of cell membrane. Cholesterol is the precursor for the synthesis of all other steroids in the body (steroid hormones, Vit D & bile acids ) It is an essential ingredient in the structure of lipoproteins in which form the lipids in the body are transported. Fatty acids are transported to liver as cholesteryl esters for oxidation.

16. Degradation of Cholesterol The steroid nucleus (ring structure) of cholesterol cannot be degraded to CO 2 and H 2 O. Cholesterol (50%) is converted to bile acids (excreted in feces), serves as a precursor for the synthesis of steroid hormones, vitamin D, coprostanol and cholestanol . Synthesis of Vitamin D: 7-Dehydrocholesterol ,an intermediate in the synthesis of cholesterol, is converted to cholecalcifero l (vitamin D 3 ) by ultraviolet rays in the skin.

17. Synthesis of Bile acids: The bile acids possess 24 carbon atoms, 2 or 3 hydroxyl groups in the steroid nucleus and aside chain ending in carboxyl group. Bile acids are amphipathic in nature. They serve as emulsifying agents in the intestine & participate in the digestion and absorption of lipids. Bile acid synthesis takes place in the liver. In the bile, the conjugated bile acids exist as sodium and potassium salts which are known as bile salts

18. Synthesis of steroid hormones from cholesterol: Cholesterol is the precursor for the synthesis of all the five classes of steroid hormones Glucocorticoids ( eg : cortisol ) Mineralocorticoids ( eg : aldosterone ) Progestins ( eg : progesterone) Androgens ( eg : testosterone) Estrogens ( eg : estradiol ).

19. Hypercholesterolemia Increase in plasma cholesterol (> 200 mg/dl) concentration is known as hypercholesterolemia. It is observed in many disorders like Diabetes mellitus, Hypothyroidism, Obstructive jaundice, Nephrotic syndrome. Control of hypercholesterolemia: (1)Consumption of poly unsaturated fatty acids (PUFA) (2)Dietary cholesterol : avoid cholesterol rich foods. (3)Plant sterols : Certain plant sterols and their esters reduce plasma cholesterol levels. They inhibit the intestinal absorption of dietary cholesterol. (4)Dietary fiber : Fiber present in vegetables decreases the cholesterol absorption from the intestine

20. (5)Avoiding high carbohydrate diet (6) lmpact of lifestyles : Elevation in plasma cholesterol is observed in people with smoking, abdominal obesity, Iack of exercise, stress, high blood pressure, consumption of soft water etc. Therefore, adequate changes in the lifestyles will bring down plasma cholesterol. (7) Moderate alcohol consumption (8) Use of drugs: Drugs such as lovastatin which inhibit HMG CoA reductase and decrease cholesterol synthesis. Certain drugs- cholestyramine and colestipol -bind with bile acids and decrease their intestinal reabsorption . Clofibrate increases the activity of lipoprotein lipase and reduces the plasma cholesterol and triacylglycerols .

21. Atherosclerosis Disease characterized by thickening or hardening of arteries due to the accumulation of lipids, collagen, fibrous tissue, calcium deposits etc. in the inner arterial wall. Atherosclerosis is a progressive disorder that narrows and ultimately blocks the arteries. The development of atherosclerosis and the risk for the coronary heart disease (CHD) is directly correlated with plasma cholesterol and LDL . Certain diseases like diabetes mellitus, hyperlipoproteinemias , nephrotic syndrome, hypothyroidism etc. are associated with atherosclerosis.

22. Many other factors like obesity, high consumption of saturated fat, excessive smoking, lack of physical exercise hypertension, stress etc., are the probable causes of atherosclerosis. The increased levels of plasma HDL (good cholesterol) are correlated with a low incidence of cardiovascular disorder . Strenuous physical exercise, moderate alcohol intake, consumption of unsaturated fatty acids (vegetable and fish oils), reduction in body weight-all tend to increase HDL levels and reduce the risk of cardiovascular disease. Antioxidants (vitamins E and C or β -carotene) reduces the risk of atherosclerosis , and thereby CHD.

23. Fatty liver Fatty liver: Excessive accumulation of Triacylglycerols in liver. In the normal liver, Kupffer cells contain lipids in the form of droplets. In fatty liver, droplets of triacylglycerols are found in the entire cytoplasm of hepatic cells. This causes impairment in metabolic functions of liver . Fatty liver is associated with fibrotic changes and cirrhosis Fatty liver may occur due to two main causes. Increased synthesis of triacylglycerols Impairment in lipoprotein synthesis.

24. Diabetes mellitus, starvation, alcoholism and high fat diet are associated with increased mobilization of fatty acids that often cause fatty liver. Fatty caused by impaired lipoprotein synthesis may be due to a defect in phospholipid synthesis; a block in apoprotein formation a failure in the formation/secretion of lipoprotein. Certain chemicals (e.g. ethionine , carbon tetrachloride, lead, chloroform , phosphorus etc.) that inhibit protein synthesis cause fatty liver. Deficiency of vitamin E is associated with fatty liver. Selenium acts as a protective agent in such a condition. Endocrine factors : Certain hormones like ACTH, insulin, thyroid hormones, adrenocorticoids promote deposition of fat in liver .

25. Obesity Obesity is an abnormal increase in the body weight due to excessive fat deposition. Overeating -coupled with lack of physical exercise -contribute to obesity. Clinical obesity is represented by body mass index (BMI). BMI (kg/ m 2 ) = Weight (kg) Height (m 2 ) Obesity is categorized into three grades: Grade I obesity or overweight - BMI 25-30 kg/ m 2 . Grade ll or clinical obesity - BMI > 30 kg/ m 2 Grade lll or morbid obesity - BMI > 40 kg/m 2

26. Obesity is associated with many health complications e.g . type ll diabetes , CHD, hypertension, stroke, arthritis, gall bladder diseases. obesity has genetic basis . Thus, a child born to two obese people has about 75% chances of being obese Leptin is regarded as a body weight regulatory hormone. (This signals to restrict the feeding behavior and limit fat deposition) Any genetic defect in leptin or its receptor will lead to extreme overeating and massive obesity. White adipose tissue : The fat is mostly stored and this tissue is metabolically less active. Brown adipose tissue : The stored fat is relatively less but the tissue is metabolically very active. Brown adipose tissue is almost absent in obese persons