Cholesterol and Fatty Liver PDF

Cholesterol metabolism and Fatty Liver ASS Professor Rasha Ghazala Medical Biochemistry  Students’ learning outcomes By the end of this lecture, the students should be able to: -Illustrate how acetyl CoA for cholesterol biosynthesis is shuttled from mitochondria to...

Cholesterol metabolism and Fatty Liver ASS Professor Rasha Ghazala Medical Biochemistry  Students’ learning outcomes By the end of this lecture, the students should be able to: -Illustrate how acetyl CoA for cholesterol biosynthesis is shuttled from mitochondria to cytoplasm 2-Illustrate reaction of cholesterol biosynthesis pathway and identify the key enzyme of the pathway and its regulation. 3- Define fatty liver and hypothesize causes 4-Define lipotropic factors and enumerate them  CHOLESTEROL Concentration in plasma of healthy people is 150-200 mg/dl * 30% of total circulating cholesterol are free *70% exists in the form of cholesterol esters with a long chain fatty acid, usually linoleic acid; these esters are solubilized in plasma lipoproteins, LDL & HDL. Sources: # Diet. # Synthesized denovo in the cytoplasm of all humans cells especially in liver , intestine, adrenal cortex and reproductive organs. Synthesis of cholesterol needs: 1- Carbon source: AcetylCoA in cytosol (supplied by citrate shuttle = acetylCoA shttle) Asp TA 2- Hydrogen source: NADPH +H supplied by * Pentose Phosphate Pathway. * Malic enzyme. * Extramitochondrial isocitratre dehydrogenase Cholesterol Regulation of cholesterol synthesis: I- Allosteric regulation (feed back inhibition): * Dietary cholesterol inhibits HMG-CoA reductase. II- Hormonal regulation: * Insulin increases the activity of HMG-CoA reductase by dephosphorylation * Glucagon decreases its activity by phosphorylation. III- Long term regulation: *Cholesterol Represses HMG-CoA reductase synthesis (inhibits transcription of HMG-CoA reductase). * Insulin Induction -Non-hepatic cells obtain cholesterol from the plasma LDL rather than by synthesizing it. - LDL uptake occurs by receptor mediated mechanism. -Receptor-LDL complex fuses with lysosomes. - cholesterol esters are hydrolyzed by lysosomal acid lipase to free cholesterol that is either. * Used unesterified for biosynthesis of cell membrane, or * Reesterified for storage inside the cell by ACAT Functions of cholesterol: # In specialized tissues, cholesterol serves as precursor of: 1- steroid hormones (e.g. in suprarenal) 2- bile salts (in liver) 3- vitamin D3. # Cholesterol is a membrane component (+ phospholipids). Mechanism of Action of HMG CoA Reductase Inhibitors(statins) The ability of statins to reduce both LDL and VLDL lipoproteins in patients with type 2 diabetes mellitus and dyslipidemia characterized by overproduction of apoB- expressing lipoproteins(LDL,VLDL) HMG CoA reductase inhibitors( Statins )bind reversibly to HMG CoA reductase and inhibit the catalytic enzyme that regulates the conversion of HMG CoA to mevalonate In response to a reduction in intracellular cholesterol, increased expression of the LDL-Receptor gene which results in increased surface expression of LDL-Receptors with increased clearance of lipoproteins. Lipotropic factors Are substances that help the mobilization of fat from the liver. They include substances essential for the biosynthesis of phospholipids and proteins.They help the formation of VLDL (for the mobilization of TG from the liver) and HDL Lipotropic factors 1. Substances important for the biosynthesis of phospholipids Essential fatty acids Inositol Choline. 2. Methyl donors Methionine Glycine betaine Vitamin B12 and folic acid. Methyl group donors are needed for synthesis of choline and carnitine 3. Pantothenic acid for synthesis of CoA which is needed for F.A. oxidation and esterification. 4. Proteins of high biological value to provide essential amino acids for the biosynthesis  Fatty liver It is the accumulation of lipid (TG) in the liver, leading to fibrotic changes and impaired liver functions. I - Causes related to lipid: A) excessive mobilization of fat to liver: Excessive intake of lipid and carbohydrate in diet. Excessive mobilization of fat from adipose tissue to the liver. TG synthesis in the liver exceeds the rate of lipoprotein formation and secretion, thus the hepatic content increases. Alcoholism: Alcohol intake increases TG and cholesterol synthesis B) Causes due to decreased mobilization of fat from the liver: deficiency of lipotropic factors e.g. methionine, choline, ethanolamine, serine and inositol. Reduced oxidation of fatty acid in the liver e.g. due to pantothenic acid and carnitine deficiency. deficiency of essential fatty acids or cholesterol overfeeding. Cholesterol is esterified with essential fatty acids resulting in their depletion and inhibition of phospholipids formation.  II - Causes related to protein: Liver poisons e.g. carbon tetrachloride - affect the conjugation of lipid to proteins to form lipoproteins - inhibit the formation of protein part of lipoproteins. Decreased intake of protein. Drugs that inhibit protein synthesis e.g. puromycin. this will lead to deficiency in lipoproteins produced by the liver  Fatty liver and cardiovascular disease (CVD): Fatty liver and cardiovascular disease (CVD) share several risk factors: obesity, metabolic syndrome, hypertension, dyslipidemia, type 2 diabetes, and chronic kidney disease., involving a range of factors from genetics to lifestyle and energy balance. Fatty liver related CVS complication: Summary Acetyl CoA for cholesterol biosynthesis is shuttled from mitochondria to cytoplasm cholesterol biosynthesis pathway end by mevalonate and the key enzyme of the pathway HMG COA reductase and its regulation is allosteric and hormonal. Fatty liver and hypothesis of its development Lipotropic factors include factors related to lipid and to protein Fatty liver is related to CVD Learning resources Harper illustrated biochemistry 31st edition Lippincott illustrated reviews biochemistry.