Cholesterol a biomolecule Bad cholesterol a strange tale Good cholesterol - indeed

Transcription

1 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

2 Cholesterol: the good, the bad, and the ugly Good Cholesterol Bad Cholesterol Ugly Cholesterol Fall2015 OLLI 2

3 Cholesterol: its just a molecule Cholesterol Fall2015 OLLI 3

4 Cholesterol a biomolecule Bad cholesterol a strange tale Good cholesterol - indeed Fall2015 OLLI 4

5 Cholesterol a biomolecule What is cholesterol? Where are the origins of cholesterol? Who transports cholesterol? What role(s) has cholesterol? Fall2015 OLLI 5

6 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

7 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

8 Origins of Cholesterol: Biosynthesis 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 Fall2015 OLLI 8

9 Mevalonate 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 Fall2015 OLLI 9

10 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

11 Cholesterol Fall2015 OLLI 11

12 Origins of Cholesterol: Cellular Uptake Fall2015 OLLI 12

13 Regulation of Cholesterol Origins 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 Fall2015 OLLI 13

14 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

15 Cholesterol Transport Fall2015 OLLI 15

16 Cholesterol Transport Liver VLDL Blood Serum Lipid removal LDL t 1/2 = 2-4 d Tissue HDL Tissue Synthesis of steriods, bile acids etc LDL binds LDL receptor internalized delivery of cholesterol Fall2015 OLLI 16

17 Cholesterol Transport - Lipoproteins 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 Fall2015 OLLI 17

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20 HDL vs LDL Fall2015 OLLI 20

21 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

22 Isoprenoid Metabolism Fall2015 OLLI 22

23 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 Testosterone Estradiol Fall2015 OLLI 23

24 Glucocorticoid Hormones Synthesized in the adrenal cortex. Regulate metabolism of carbohydrates. Decrease inflammation and mediate stress Fall2015 OLLI 24

25 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. H 3 C H 3 C HO CH 3 O NH COO - H 3 C H 3 C HO CH 3 O NH SO 3 2- HO OH Glycocholate (from glycine) HO OH Taurocholate (from taurine) Fall2015 OLLI 25

26 Vitamin D, A, E, and K Vit K Vit A Vit D Vit E Fall2015 OLLI 26

27 Ubiquinone Ubiquinone is an essential electron transporter of cellular respiration Enables switch from 2 to 1 e - transport onto oxygen. Fall2015 OLLI 27

28 Biological Membranes Complex lipids including cholesterol form the membranes around cells and subcellular structures Compartmentalization of biological processes Membranes are flexible, self-sealing, selectively permeable Fall2015 OLLI 28

29 Biological Membranes are heterogeneous Fall2015 OLLI 29

30 Biological Membranes - Fluidity (b) Fluid state Fall2015 OLLI 30

31 Cholesterol and Membranes Found in varying amounts throughout the membrane Stiffen and Strengthen membranes due to its sterol group Fall2015 OLLI 31

32 Lipid Rafts - rigid platforms Fall2015 OLLI 32

33 Lipid Rafts: Communication Portals Fall2015 OLLI 33

34 Cholesterol a chaperone Fall2015 OLLI 34

35 Cholesterol a chaperone Fall2015 OLLI 35

36 Cholesterol a chaperone Fall2015 OLLI 36

37 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

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40 Cholesterol HIV infection gp41 mediates binding of HIV virus to cell membranes Cholesterol interaction with gp41 is necessary for virus entry Fall2015 OLLI 40

41 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

42 The official messages NHLBI WebMD (specifically recommended by my health insurance) American Heart Association Fall2015 OLLI 42

43 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

44 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 Less than 200mg/dL - Desirable mg/dl - Borderline high 240mg/dL and above High Triglycerides normal < 150 mg/dl Borderline mg/dl High mg/dl Risk > 500 mg/dl Total LDL Less than 100mg/dL - Optimal mg/dL - Near optimal mg/dl - Borderline high mg/dl - High 190 mg/dl and above - Very High Total HDL Less than 40 mg/dl - major risk mg/dl - better over 60 mg/dl protective Fall2015 OLLI 44

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46 Cholesterol Guidelines 88% of NCEP members are directly paid by the pharmaceutical industry Fall2015 OLLI 46

47 Facts about LDL and HDL 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) Fall2015 OLLI 47

48 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

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