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Uploaded byFarhana Atia
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Cholesterol Metabolism

This document discusses cholesterol, including that it is a major sterol in animal tissues, is both obtained through diet and synthesized in the body, and serves various structural and metabolic functions. It describes cholesterol biosynthesis occurring primarily in the liver, intestine, and other tissues, requiring acetyl-CoA, ATP, and NADPH. The rate-limiting enzyme HMG-CoA reductase is regulated by feedback and hormones. Factors like genetics, diet, lifestyle, and drugs can affect serum cholesterol levels. Disorders like familial hypercholesterolemia involve inherited defects in lipid metabolism and LDL receptors, elevating LDL and total cholesterol and increasing atherosclerosis risk.

Health & Medicine◦
CHOLESTEROL No vegetable oil contains any cholesterol Cholesterol is the major sterol in animal tissues Total cholesterol in a 70 kg man: 140 gm (2gm/kg) A portion of the body cholesterol is derived from diet (egg yolk, meat, liver brain) A little more than half of it is synthesized in the body (700 mg/d)
Structural component of cell membrane Steroid hormone (Progesterone, estrogens, glucocorticoid, mineralocorticoids) Vitamin D (from 7-dehydrocholesterol) Bile acids (Cholic acid, Chenodeoxycholic acid) Transport of fatty acid to liver as cholesteryl esters (plasma lipoproteins)
CHOLESTEROL BIOSYNTHESIS • Virtually all tissues containing nucleated cells are capable • Occurs in ER and cytosol • Site: Liver (10%), Intestine (10%), Adrenal cortex, Reproductive tissues, Skin • All the carbon atoms of cholesterol are derived from acetyl CoA • Requirements: Acetyl CoA- 18 moles ATP- 36 moles NADPH- 16 moles
STEPS OF DE NOVO CHOLESTEROL SYNTHESIS • Step 1—Biosynthesis of Mevalonate (6C) • Step 2—Formation of Isoprenoid Units (5C) • Step 3—Six Isoprenoid Units Form Squalene (30C) • Step 4—Formation of Lanosterol (30C) • Step 5—Formation of Cholesterol (27C)
Acetoacetyl-CoA HMG-CoA Several steps Cholesterol • First 2 steps are similar as ketone body synthesis • But KB synthesis occurs in mitochondria
HMG-COA REDUCTASE  Rate limiting enzyme  Present in endoplasmic reticulum Regulated by- • Feedback control (mevalonate, cholesterol) • Hormonal regulation Insulin, thyroxin (+) • Drugs (Statins) Glucagon, glucocorticoid (-) • Bile acids, fasting
HMG-CoA reductase (active) HMG-CoA reductase (Inactive) Acetyl-CoA HMG-CoA Mevalonate CHOLESTEROL Insulin Glucagon Increased caloric intake, Thyroid hormone Bile acids, glucocorticoids, Dietary cholesterol P Dephosphorylation Phosphorylation + + + - REGULATION OF DE NOVO SYNTHESIS OF CHOLESTEROL
EXCRETION OF CHOLESTEROL • Cannot be destroyed by oxidation to CO2 and H2O, because of absence of enzyme capable of catabolising the steroid nucleus • 50% is converted to bile acid • Cholesterol is excreted in faeces • About 1gm of cholesterol is eliminated from the body per day (C-0.6g/d; bile acid-0.4 g/d)
BLOOD CHOLESTEROL Plasma cholesterol is associated with different lipoprotein fraction (LDL, HDL, VLDL) Free cholesterol -30%; Ester with long chain FA as cholesteryl ester- 70% Major constituent of gall stone; correlated with atherosclerosis & CHD Blood levels are influenced by both genetic and environmental factors
FACTORS AFFECTING SERUM CHOLESTEROL LEVEL • Hereditary factors • Diet • Beneficial- Unsaturated fats (ω₆, ω₃ FA) • Harmful- Saturated fat, sucrose, fructose • Lifestyle- High blood pressure, smoking, male gender, obesity, lack of exercise, soft drinks, emotional stress • Hypolipidemic drug (atorvastatin, simvastatin, Fluvastatin)- when diet change fail
DISORDER OF CHOLESTEROL METABOLISM Familial Hypercholesterolemia Inherited defects in LP metabolism Deficiency or malfunction of LDL receptors Plasma LDL & cholesterol level are elevated Atherosclerosis Deposition of cholesterol and other lipids in the arterial wall Leads to formation of plaque → endothelial damage → IHD
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