Cholesterol Metabolism PDF

Molecular Fundamentals of Medicine Cholesterol Metabolism Relevant Reading: Mark’s Basic Medical Biochemistry 1/7/25 Chap. 32 1 1  Learning Objectives Describe the str...

Molecular Fundamentals of Medicine Cholesterol Metabolism Relevant Reading: Mark’s Basic Medical Biochemistry 1/7/25 Chap. 32 1 1  Learning Objectives Describe the structure/functions of cholesterol. List the important intermediates of de novo synthesis. Discuss the regulation of intracellular cholesterol: – Describe how HMG-CoA reductase is regulated. Describe the fates of cholesterol. – Explain the mechanisms governing cholesterol metabolism and excretion. – Describe the bile acids and their enterohepatic circulation. Describe dietary treatment strategies for hyperlipidemias. 1/7/25 2 2  Structure of Cholesterol Structure consists of four fused hydrocarbon rings (A-D) called “steroid nucleus” Cholesterol contains a hydroxyl group at C3, double bond between C5 & C6, eight-membered hydrocarbon chain at C17, & methyl groups at C10 & C13 1/7/25 3 3  Cholesterol Functions Membrane component Precursor to - Bile acids - Vitamin D - Steroid hormones Humans cannot metabolize cholesterol to CO2 and water. The balance between cholesterol influx and efflux is not precise, resulting in gradual deposition of cholesterol in the tissues. The lipid deposition in the endothelial linings of blood vessels may lead to plaque formation, causing narrowing of blood vessels (atherosclerosis) and increase risk of cardio-, cerebra-, and peripheral vascular disease. 1/7/25 4 4  The free and esterified cholesterol Most cholesterol in cellular membranes is present in the free form. Dietary cholesterol brought to liver is mostly free cholesterol. Most of the circulating cholesterol exists esterified to Site of a long-chain fatty acids esterification (oleic, linoleic) 1/7/25 5 5  The esterified cholesterol Two key enzymes can esterify cholesterol. Acyl-CoA:cholesterol acyl transferase (ACAT) is an ER membrane protein ACAT transfers fatty acid from fatty acyl-CoA to C3 hydroxyl group of cholesterol. Excess cholesterol is stored as cholesterol esters in cytosolic lipid droplets. The other is an extracellular enzyme lecithin:cholesterol acyltransferase (LCAT), which esterifies cholesterol associated with the HDL. 1/7/25 6 6  De novo Synthesis of Cholesterol Primary site: liver (~1g/day) within the cell, in the SER. Secondary sites: intestine, adrenal cortex, ovaries, testes – The brain is the most cholesterol-rich organ of the body. All cholesterol in the brain is synthesized within the central- nervous system. Cholesterol synthesis high during active myelination. All carbons come from acetyl-CoA. HMG-CoA reductase is the rate limiting, committing step and is regulated by: – transcriptional control – proteolytic degradation – covalent modification Requires 18 Acetyl-CoA, 16 NADPH, 36 ATP, & O2 1/7/25 7 7  Sources of Acetyl CoA Pyruvate dehydrogenase reaction (Glucose) Ethanol Nearly all of the Acetyl CoA is generated in mitochondria, the acetyl moieties are transported to cytosol in the form of citrate. 1/7/25 8 8  De novo Synthesis of Cholesterol In the cytosol In the ER Synthesis of mevalonate from cytosolic AcCoA. Three AcCoA condense to form HMG-CoA. The cytosolic HMG-CoA synthase in this pathway is distinct from the mitochondrial isoenzyme which catalyzes HMG- CoA synthesis for ketone body synthesis. HMG-CoA reductase converts HMG-CoA to mevalonate in the ER. 1/7/25 9 9  Mevalonic acid is phosphorylated and decarboxylated to form an isoprenoid. Five-carbon isoprenoids condense to form farnesyl pyrophosphate. Squalene is formed from two 15-carbon farnesyl pyrophosphate units and then oxidized and cyclized forming lanosterol. Lanosterol is converted to cholesterol. 1/7/25 10 10  Fate of hepatic cholesterol Transport to extra-hepatic tissues. Cholesterol is esterified by ACAT (Acyl-CoA Cholesterol Acyl Transferase) and packed into VLDL. Direct excretion into gallbladder as biliary cholesterol. - most Gallstones are precipitates (cholelithiasis) of cholesterol and occur when bile becomes supersaturated with cholesterol (obesity, biliary stasis, infections). Bile acid synthesis and excretion into bile. 1/7/25 11 11  Synthesis of Bile Acids (24 C) Synthesized in the liver Stored & concentrated in the gallbladder Discharged into gut and aides in absorption of lipids, cholesterol, & fat soluble vitamins Rate-limiting step performed by the 7α-hydroxylase (CYP7A1) and is regulated by bile acid & salt concentration. End products: Cholic acid series & Chenocholic acid series Bile acids can be conjugated & become better detergents 12 1/7/25 12  Conjugation of Bile Acids Some bile salts are conjugated to a glycine or taurine Major role in digestion and absorption. They emulsify dietary lipids and stabilize mixed micelles. Lipids have low water solubility and are dependent on bile salts for their absorption. 1/7/25 13 13  Fate of the Bile Salts 1/7/25 14 14  Regulation of HMG-CoA Reductase Activity Cholesterol synthesis is a complex, energy-expensive process and is regulated by: 1. Transcriptional regulation 2. Proteolytic degradation of HMG-CoA Reductase 3. Regulation by covalent modification 1/7/25 15 15  Hormonal Regulation via Insulin/Glucagon: phosphorylation/dephosphorylation 3. Glucagon: phosphorylation inactivates the HMG-CoA reductase. Hyperinsulinemia: increases the activity of the reductase by activating phosphatases. 1/7/25 16 16  Cholesterol lowering drug: HMG-CoA Reductase Inhibitors – Statins are structural analogs of HMG-CoA: 18-55% reduction in LDL-C HDL increases and TG decreases – Proposed mechanism of action HMG-CoA analog is a competitive inhibitor of HMG-CoA reductase. Inhibition of cholesterol synthesis reduces intracellular cholesterol pool and up-regulates the synthesis of LDL-receptors 1/7/25 17 17 1/7/25 18 18  Treating Hypercholesterolemia by diet Reducing intake of dietary saturated fat. No trans-fatty acids. Reduce intake of dietary cholesterol. Increase consumption of viscous soluble dietary fiber. – Impairs absorption of dietary cholesterol, and bile acids. Consume therapeutic doses of plant sterols and stanols. – Inhibits absorption of dietary cholesterol and reabsorption of cholesterol in bile. 1/7/25 19 19 1/7/25 20 20  Bile acid sequestrants (cholestramine) – Reduces LDL by 15-30%: Insoluble, nonabsorbable anion exchanger binds bile acids in the intestine and prevents reabsorption of bile acids. Increases hepatic synthesis of bile acids, 7-α- hydroxylase activity is increased. reduces cholesterol pool, up-regulates LDL-receptors. – Side effects: GI distress, constipation, decreased absorption of lipid-soluble vitamins and other drugs. 1/7/25 21 21  Pharmacological doses of NIACIN for treating hypercholesterolemia: – 5-25% reduction in LDL Increases HDL, decreases LDL – Proposed mechanism Reduces VLDL synthesis in liver Decreases lipolysis in adipose Increases Lipoprotein Lipase activity Decreases TG in liver – Side effects: flushing, itching, GI distress, hyperglycemia, hyperuricemia, hepatotoxicity Page 621 Cora Nari 1/7/25 22 22  common Statin Drugs 1/7/25 23 23  Transcriptional control 1. The synthesis rate of HMG-CoA reductase mRNA is controlled by sterol-regulatory element-binding proteins (SREBPs). SREBP is an ER membrane protein and associates with SCAP (SREBP cleavage-activating protein). When sterol is low SREBP-SCAP complex is sent out of the ER to the Golgi, where SREBP is released from SCAP by proteolytic cleavage and enters to nucleus. SREBP binds to DNA (SRE) and activates HMG-CoA reductase gene expression. 1/7/25 24 24 Plant stanols No double bond on B ring Plant sterols Different side chains 1/7/25 25 25 1/7/25 26 26