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Lecture38_Raetz - Chris Raetz Department of Biochemistry...

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Unformatted text preview: Chris Raetz Department of Biochemistry Sands Building Room 244A 684-3384 [email protected] Biochemistry 227 December 6, 2010 Cholesterol Homeostasis Lehninger (5th Edition) Ch. 21 pp. 831-845 For discussion sections: Cholesterol Problems 1 Cholesterol homeostasis Total body cholesterol ~50 gm Plasma cholesterol ~200mg/100ml (5 mM) Dietary cholesterol ~ 200 - 400 mg/day Endogenous cholesterol biosynthesis Endogenous (mainly liver) ~ 700 - 1000 mg/day 700 Cholesterol lost from the body (bile acids and cholesterol) ~ 900 - 1400 mg/day 2 Some Definitions • Lipoprotein = a macromolecular complex of proteins with cholesterol, cholesterol esters, triglycerides and phospholipids. • Apoprotein = a specific protein that is integrated into a lipoprotein complex. Often, it has enzymatic or receptor-ligand functions. • Chylomicron = a large lipoprotein made chiefly of triglycerides that is made in the GI tract to ship dietary lipids to the liver. After eating a fatty meal, chylomicrons flood the 3 bloodstream visibly increasing the turbidity of plasma. Some More Definitions • VLDL = a lipoprotein made in the liver to ship lipids to peripheral tissue. Marked by large size and Apo B-100. • LDL = a VLDL from which most of the triglycerides have been removed. Smaller and high in cholesterol esters. • HDL = smallest lipoprotein consisting mostly of protein and some cholesterol esters. “Good cholesterol” marked by Apo A & D. Model of lipoprotein 4 Two Source of Cholesterol Esters A. B. Size Matters (For Lipoproteins) 6 Lipoprotein Composition 7 Lipoprotein Composition Lipoproteins in Circulation • Chylomicrons – Formed in gut – Go to liver • VLDLs – Formed in liver – Go to periphery • LDLs & IDLs – Formed in periphery • “VLDL remnants” – Return to Liver • HDLs – Precursors are made in liver&intestine – Formed in periphery – Go to liver 9 Note: Liver can dump excess cholesterol into bile. Familial Hypercholesterolemia • You are a pediatrician. A 14-year-old male presents with “growths” on his ankles and knees (see pictures). He appears in good health, but questioning reveals that during exercise he easily becomes winded and has chest pain. Blood tests show his LDL cholesterol is 931 mg/dL. His mom’s is 477 and his dad’s is 502. (Normal is 120 or less; about 2/3 of the circulating cholesterol.) What is wrong? “Growths” over the patient’s patellar and Achilles tendons. Called “tendon xanthomas” they are a hallmark sign of biochemical dysfunction. 10 • • • LDL and Its Role in Familial Hypercholesterolemia Features of FH • Autosomal co-dominant • Heterozygotes - 2-4x higher LDL Heterozygotes • Homozygotes - 6-10x higher LDL Homozygotes • 1/500 are heterozygotes 1/500 11 Binding & Endocytosis of LDL by the LDL Receptor by Normal Liver Cells and/or Fibroblasts LDL Receptor Synthesis LDL HMG-CoA Redcutase Chol. esterification Chol. (ACAT) (ACAT) 12 Cholesterol homeostasis (balance of endogenous versus dietary) begins in Endoplasmic Reticulum Cholesterol LDL Processing in Normal versus FH Fibroblasts 13 Structure of the LDL Receptor LDL binding sites (Cysteine rich) N-terminus (# AA residues) ~322 (# ~350 58 22 50 Cytoplasm C-terminus Plasma membrane Domains 14 Transcriptional and proteolytic regulation of cholesterol homeostasis LDL Receptor: 1. Transcription is repressed at high cholesterol levels. 2. A serum protease, PCSK9, reduces LDL-R levels. Rare individuals lacking PCSK9 exist and have less coronary artery disease. N Engl J Med. (2008) 358:2299-300. HMG-coenzyme A reductase: 1. Transcription is repressed at high cholesterol levels. 2. Proteolysis is accelerated by high cholesterol. 3. Additional regulatory mechanisms exist. Other enzymes: also regulated at the level of transcription 15 Sterol Regulated Promoters SRE (Sterol regulatory element) SREBPs (SRE binding proteins) inding Three related types: 1a, 1c, and 2 16 Proteolytic Release of SREBPs and Role of SCAP SCAP: SREBP cleavage activating protein: See J. Clin. Invest. 109:1125-31, 2002 109:1125-31, N-terminus N-terminus Site 2 Site 1 17 Proteolytic Release of SREBP: Roles of SCAP and INSIG SCAP: SREBP cleavage activating protein; INSIG: insulin-induced gene See PNAS 104:6511-26, 2007 104:6511-26, 18 Lipid Engorged Livers of Transgenic Mice Over-expressing Mature SREBP-1a Wild Type Transgenic SREBP-1a 1-470 19 19 Role of SREBPs in Global Regulation of Lipid Metabolism Role SREBP1a works equally at all promoters. See J. Clin. Invest. 109:1125-31, 2002 109:1125-31, 20 How Lovastatin and Related Statin Drugs Work nitial dosing (20 - 80 mg/day) partially blocks cholesterol synthesis in liver. eripheral tissues are spared (drug distribution effect). ranscriptional and post-transcriptional mechanisms restore cholesterol levels n liver. (Increased biosynthetic enzymes, increased LDL receptors). levated LDL receptors in liver lower LDL concentrations in plasma. fter 1 - 2 weeks, 80 mg/day lowers total and LDL cholesterol by 35 - 45 %. fter holesterol deposits in coronary arteries no longer expand vs. placebo (2 yrs). holesterol bout 40 % lowering of second heart attacks in patients with heart disease. eople without previous heart disease also benefit greatly. dditional benefits from lowering of non-sterol products ? Rapid onset of cardiovascular benefits in clinical trials. 21 Statins reduce coronary mortality New England Journal of Medicine, Nov. 16, 1304 (1995) New 22 Typical Time Course of Drug Discovery 23 ...
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