Cholesterol – a biomolecule Bad cholesterol – a strange tale Good cholesterol - indeed Thomas B. Kuhn: University of Alaska, Cereon Biotechnology LLC This document is protected by copyright © Dr. Thomas B. Kuhn All rights reserved Fall2015 OLLI 1 Cholesterol: the good, the bad, and the ugly Bad Cholesterol Good Cholesterol Ugly Cholesterol Fall2015 OLLI 2 Cholesterol: its just a molecule Cholesterol Fall2015 OLLI 3 Cholesterol – a biomolecule Bad cholesterol – a strange tale Good cholesterol - indeed Fall2015 OLLI 4 Cholesterol – a biomolecule What is cholesterol? Where are the origins of cholesterol? Who transports cholesterol? What role(s) has cholesterol? Fall2015 OLLI 5 What is Cholesterol? Cholesterol is a Lipid Cholesterol is synthesized by all cells Cholesterol is taken up from extracellular sources (food) Cholesterol is vital for membrane integrity Cholesterol is a precursor for a plethora of biomolecules 25% of all Cholesterol is in the brain ! Fall2015 OLLI 6 What is Cholesterol? Cholesterol is synthesized by our body Cholesterol is ingested through food sources Cholesterol has 27 carbon atoms All carbon atoms are derived from isoprene (C5 unit) Isoprene is generated from acetate Fall2015 OLLI 7 Origins of Cholesterol: Biosynthesis Fall2015 4 major steps 4 major intermediates Acetate - the starting unit, most common metabolite Mevalonate – key precursor to generate isoprene Isoprene – curcial building block for many biomolecules Squalene – principal carbon skeleton for all sterol-like compounds OLLI 8 Mevalonate Fall2015 2 Acetates are fused to a ketone body Additional condensation of an acetate generates β-hydroxy-βmethylglutarate Reduction of β-hydroxy-βmethylglutarate by HMG-CoA reductase, HMG-CoA reductase is the key regulatory site of cholesterol synthesis OLLI 9 Squalene Consecutive condensation of isoprene (5 carbons) Geranyl (2 isoprenes, 10 carbons or 2x 5 carbons) Farnesyl (3 isoprenes, 15 carbons or 3 x 5 carbons) Squalene (2 farnesyl, 30 carbons = 2 x 15 carbons) Fall2015 OLLI 10 Cholesterol Fall2015 OLLI 11 Origins of Cholesterol: Cellular Uptake Fall2015 OLLI 12 Regulation of Cholesterol Origins Fall2015 OLLI HMG-CoA reductase – classic feedback inhibition Sufficient Cholesterol signals cholesterol esters, blocks up take, and blocks synthesis Transcriptional via the Sterol regulatory element-binding proteins (SREBPs) Opposing effect of insulin and glucagon Cross talk to blood sugar levels 13 Regulation of Cholesterol Origins Uptake of cholesterol is measured by sterol-sensing protein Binding of cholesterol to sterol sensing protein initiates degradation of HMG-CoA reductase Fall2015 OLLI 14 Cholesterol Transport Fall2015 OLLI 15 Cholesterol Transport Liver VLDL Blood Serum LDL Tissue Lipid t1/2= 2-4 d removal HDL Tissue Synthesis of steriods, bile acids etc LDL binds LDL receptor – internalized – delivery of cholesterol Fall2015 OLLI 16 Cholesterol Transport - Lipoproteins Fall2015 Cholesterol like other lipids virtually water insoluble Plasma lipoproteins are carriers Apoprotein (ApoB-100) in complex with lipids Lipoprotein complexes vary in density reflecting distinct functions Major Apolipoproteins are B and E OLLI 17 Fall2015 OLLI 18 Fall2015 OLLI 19 HDL vs LDL Fall2015 OLLI 20 Roles of Cholesterol Precursor of many biomolecules Major component of cell membranes Impacts cell membrane fluidity Organizes cell membranes Chaperone for protein function Fall2015 OLLI 21 Isoprenoid Metabolism Fall2015 OLLI 22 Steroid Hormones Cholesterol is the starting material for the synthesis of all steroid hormones Cholesterol is converted to progesterone Progesterone serves as precursor for other steroid hormones. Progesterone Fall2015 Testosterone OLLI Estradiol 23 Glucocorticoid Hormones Synthesized in the adrenal cortex. Regulate metabolism of carbohydrates. Decrease inflammation and mediate stress Fall2015 OLLI 24 Bile Salts Bile salts are oxidation products of cholesterol. Synthesized in the liver, stored in the gallbladder, and secreted into the intestine where they emulsify dietary fats and aid in their absorption and digestion. H3 C HO C H3 H3 C HO OH O H3 C HO C H3 NH C O O- H3 C HO Glycocholate (from glycine) Fall2015 OLLI O NH S O3 2 - OH Taurocholate (from taurine) 25 Vitamin D, A, E, and K Vit K Vit A Vit D Vit E Fall2015 OLLI 26 Ubiquinone Ubiquinone is an essential electron transporter of cellular respiration Enables switch from 2 to 1 e- transport onto oxygen. Fall2015 OLLI 27 Biological Membranes Fall2015 Complex lipids including cholesterol form the membranes around cells and subcellular structures Compartmentalization of biological processes Membranes are flexible, self-sealing, selectively permeable OLLI 28 Biological Membranes are heterogeneous Fall2015 OLLI 29 Biological Membranes - Fluidity (b) Fluid state Fall2015 OLLI 30 Cholesterol and Membranes Found in varying amounts throughout the membrane Stiffen and Strengthen membranes due to its sterol group Fall2015 OLLI 31 Lipid Rafts - rigid platforms Fall2015 OLLI 32 Lipid Rafts: Communication Portals Fall2015 OLLI 33 Cholesterol – a chaperone Fall2015 OLLI 34 Cholesterol – a chaperone Fall2015 OLLI 35 Cholesterol – a chaperone Fall2015 OLLI 36 Cholesterol – Alzheimer’s Disease Cholesterol is necessary for the proper function of Amyloid precursor protein (APP) Alzheimer’s disease – alterations in lipid metabolism Alzheimer’s disease – alteration in lipid raft organization Fall2015 OLLI 37 Fall2015 OLLI 38 ? Fall2015 OLLI 39 Cholesterol – HIV infection gp41 mediates binding of HIV virus to cell membranes Cholesterol interaction with gp41 is necessary for virus entry Fall2015 OLLI 40 The Official Message National Heart, Lung, and Blood Institute - Mission Statement provides global leadership for a research, training, and education program to promote the prevention and treatment of heart, lung, and blood diseases and enhance the health of all individuals so that they can live longer and more fulfilling lives. stimulates basic discoveries about the causes of disease enables the translation of basic discoveries into clinical practice fosters training and mentoring of emerging scientists and physicians communicates research advances to the public to help reduce the burden of heart, lung, and blood diseases worldwide. Fall2015 OLLI 41 The official messages NHLBI WebMD (specifically recommended by my health insurance) American Heart Association Fall2015 OLLI 42 Cholesterol Guidelines The National Cholesterol Education Program (NCEP) is a program managed by the NHLB institute (NIH) with the goal to reduce increase Cardiovascular Disease (CVD) to due elevated cholesterol in the US since 1985 The assigned goal of the NCEP committee is to meet on a recurring basis, review ongoing scientific research about CVD and make simplified, consensus, committee recommendations to be promoted by NIH and AHA to physicians and public to reduce CVD death Fall2015 OLLI 43 How is Cholesterol Measured Blood analysis (fasting or non fasting) Measurement of total cholesterol, LDL, HDL, and triglycerides (mg/dL or mg/100 ml) Total Cholesterol Total LDL Less than 200mg/dL - Desirable 200-239 mg/dL - Borderline high 240mg/dL and above – High Less than 100mg/dL - Optimal 100-129mg/dL - Near optimal 130-159 mg/dL - Borderline high 160-189 mg/dL - High 190 mg/dL and above - Very High Triglycerides Total HDL normal < 150 mg/dL Borderline - 150-199 mg/dL High - 200-499 mg/dL Risk > 500 mg/dL Fall2015 Less than 40 mg/dL - major risk 40—59 mg/dL - better over 60 mg/dL protective OLLI 44 Fall2015 OLLI 45 Cholesterol Guidelines 88% of NCEP members are directly paid by the pharmaceutical industry Fall2015 OLLI 46 Facts about LDL and HDL Fall2015 Most of the cholesterol is carried by LDL true Normal plasma levels are 175 mg/100 mL false (!!!!) LDL receptors necessary for LDL uptake true LDL receptors number controlled by intracellular cholesterol levels true Familial hypercholesterolemia – low LDL receptors thus high plasma cholesterol (>680 mg) true High plasma cholesterol causes premature atherosclerosis and heart attacks false!!!!! high LDL-low HDL ratio = a warning true/false serum Chol à Chol synthesis true Chol in diet directly affects Chol in blood false statin drugs inhibit Chol synthesis true (HMG-CoA reductase) OLLI 47 Cholesterol - Summary Cholesterol is vital for hormone production Cholesterol is vital for digestion (bile acids) Cholesterol is vital for membrane organization Cholesterol is vital for the brain (neurotransmitter receptors) There is little if any scientific basis that cholesterol causes heart disease Fall2015 OLLI 48 Fall2015 OLLI 49
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