Cholesterol metabolism. Function Biosynthesis Transport in the organism Hypercholesterolemia

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Tamsin Terry
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1 Cholesterol metabolism Function Biosynthesis Transport in the organism Hypercholesterolemia

- component of all cell membranes - precursor of bile acids steroid hormones vitamin D Cholesterol Sources: dietary cholesterol (~ 25% of a daily turnover) - 0,3g/day synthesis in tissues (~ 75 %) -

2 - component of all cell membranes - precursor of bile acids steroid hormones vitamin D Cholesterol Sources: dietary cholesterol (~ 25% of a daily turnover) - 0,3g/day synthesis in tissues (~ 75 %) - 1 g/day liver (reproductive tissues -adrenal cortex, ovaries, testes, placenta) enzymes of biosynthesis present in virtually all tissues Transport: chylomicrons: intestine liver VLDL: liver plasma as a component LDL: plasma extrahepatic tissues of lipoproteins, HDL: plasma liver most as cholesteryl esters (extrahepatic tissues)

3 Overview of cholesterol metabolism in liver Dietary cholesterol Chylomicron remnants De novo synthesis of cholesterol in liver Cholesterol from extrahepatic tissues HDL Secretion in HDL and VLDL Free cholesterol secreted in bile Conversion to Bile acids/salts

4 Cholesterol excretion! Steroid ring can not be cleaved in humans 1. cholesterol bile acids/salts bile intestine feces liver cholestanol 2. cholesterol bile intestine koprostanol feces Cholesterol availability in diets widely varies balance the rate: cholesterol synthesis regulatory mechanisms cholesterol excretion Imbalance: elevation of circulating cholesterol coronary artery disease excessive cholesterol excretion into bile precipitation in the gallblader and bile duct gallstones

Cholesterol biosynthesis Initial substrate: acetyl-coa Tissue localization: predominantly liver mitochondria acetyl-coa farnesyl pyrophosphate endoplasmic

5 Cholesterol biosynthesis Initial substrate: acetyl-coa Tissue localization: predominantly liver mitochondria acetyl-coa farnesyl pyrophosphate endoplasmic reticulum translokase for citrate cytosol oxaloacetate citrate isopentenyl pyrophosphate citrate acetyl-coa mevalonate HMG-CoA squalene lanosterol cholesterol

6 Cholesterol biosynthesis: acetyl-coa mevalonate O CH 3 -C-S-CoA + O CH 3 -C-S-CoA 2 x acetyl-coa acetoacetyl-coa O O CH 3 -C-CH 2 -C-S-CoA + O CH 3 -C-S-CoA HMG-CoA CoASH O CH 3 O HMG-CoA synthase - O-C-CH 2 -C-CH 2 -C-S-CoA OH CoASH HMG-CoA reductase O CH 3 - O-C-CH 2 -C-CH 2 -CH 2 -OH OH mevalonate

7 Cholesterol biosynthesis: mevalonate cholesterol

Control of cholesterol synthesis Regulation of HMG CoA reductase, rate-limiting enzyme of cholesterol synthesis SRE = sterol regulatory element SREBP = sterol regulatory binding protein transcription

8 Control of cholesterol synthesis Regulation of HMG CoA reductase, rate-limiting enzyme of cholesterol synthesis SRE = sterol regulatory element SREBP = sterol regulatory binding protein transcription factor associated with ER membrane proteolytic release binding to DNA at SRE transcription of HMG CoA reductase blocked by cholesterol 1. Regulation of transcription (HMG CoA reductase short biological half-time ~ 2 h): feed-back repression of HMG-CoA synthesis: cholesterol LDL-CH - liver, periferal cells CHR-CH liver 2. Hormonal regulation: insulin - enzyme dephosphorylation = activation, enzyme expression glukagon - enzyme phosphorylation - inactivation

9 Control of cholesterol synthesis 3. Competitive inhibition of HMG CoA reductase: statins fungal compounds or chemically synthesized therapeutic agents of similar structurelovastatin mevastatin simvastatin treatment of hypercholesterolemia binding to the active site of HMG CoA reductase

Metabolism of VLDL- and LDL-cholesterol Synthesized cholesterol packed into VLDL, VLDL converted in plasma to IDL and LDL LDL deliver cholesterol to periferal

10 Metabolism of VLDL- and LDL-cholesterol Synthesized cholesterol packed into VLDL, VLDL converted in plasma to IDL and LDL LDL deliver cholesterol to periferal tissues via LDL receptors IDL and ~75 % of LDL return back to liver, are degraded in lysosomes Released cholesterol incorporated into VLDL or converted to bile acids

11 Secretion of VLDL from the liver

12 Transport of exogenous cholesterol cholesterol TAG food intestine TAG:cholesterol ~10:1 chylomicron LPL liver TAG:cholesterol ~1:1 chylomicron -remnant free fatty acids albumin tissues

13 Transport of endogenous cholesterol VLDL free fatty acids albumin tissues liver TAG:cholesterol ~5:1 LPL extrahepatic tissues LDL TAG:cholesterol ~1:5 IDL VLDL remnants TAG:cholesterol ~5:1

LDL-receptor - provides cholesterol delivery into tissues - membrane glycoprotein - requires apob, apoe as ligands for interaction with a lipoprotein particle defective LDL-receptor LDL

14 LDL-receptor - provides cholesterol delivery into tissues - membrane glycoprotein - requires apob, apoe as ligands for interaction with a lipoprotein particle defective LDL-receptor LDL in plasma plasma cholesterol hypercholesterolemia atherosclerosis (hypercholesterolemia IIa) LDL uptake by endocytosis lysosomal digestion cholesterol (and other products) release into cell

Metabolism of HDL CETP PCAT = phosphatidylcholine:cholesterol acyltransferase (LCAT = lecithin:cholesterol acyltransferase) reverse cholesterol transport HDL

transfers cholesteryl esters to VLDL in exchange for TAG - transfer is mediated by CETP particles accept apocii from VLDL, apo E from IDL HDL 2 HDL 2 are

15 Metabolism of HDL CETP PCAT = phosphatidylcholine:cholesterol acyltransferase (LCAT = lecithin:cholesterol acyltransferase) reverse cholesterol transport HDL pick up cholesterol from periferal tissue and other lipoproteins cholesterol is esterified by LCAT, particles fill with cholesteryl esters HDL 3 HDL 3 transfers cholesteryl esters to VLDL in exchange for TAG - transfer is mediated by CETP particles accept apocii from VLDL, apo E from IDL HDL 2 HDL 2 are taken up by liver via specific receptors, endocytoced and digested in lysosomes cholesterol released into liver cell is incorporated into VLDL or converted to bile acids

Hypercholesterolemia = elevated level of cholesterol in the blood primary (genetic) defective LDL-receptor - secondary diet high in fat and cholesterol,

16 Hypercholesterolemia = elevated level of cholesterol in the blood primary (genetic) defective LDL-receptor - secondary diet high in fat and cholesterol, obesity, alcoholism, diabetes mellitus.. risk factor of atherosclerosis, associated with the formation of atherosclerotic plaques LDL atherogenic HDL protective

Unit IV Problem 3 Biochemistry: Cholesterol Metabolism and Lipoproteins

Unit IV Problem 3 Biochemistry: Cholesterol Metabolism and Lipoproteins - Cholesterol: It is a sterol which is found in all eukaryotic cells and contains an oxygen (as a hydroxyl group OH) on Carbon number