1 + Lipid Structure Cholesterol Fatty Acids TriglyceridesCOOH COO COOH COO COOH COO HO Phospholipid: Lecithin + Glycerol COO HO COO HO + N OPOO

2 (More Than Cholesterol Synthesis) Farnesyl PyrophosphateHMG CoA Reductase (More Than Cholesterol Synthesis) Acetyl CoA HMG CoA Mevalonate Farnesyl Pyrophosphate Cholesterol HMG CoA Reductase Isopentenyl adenine (transfer RNA) Prenylation of signalling peptides (ras, rho, etc.) Ubiquinones (CoQ-10, etc.) Dolichols Inhibition of other key products of mevalonate may relate to nonlipid effects & rare side effects of statins.

3 NORMAL CHOLESTEROL METABOLISMTissue pools 70G 0.8 G SYN CHOL* 0.4 G CHOL *SYN CHOL = CHOLESTEROL SYNTHESIS

4 NORMAL CHOLESTEROL METABOLISMTissue pools 70G 0.85 G ABS CHOL 0.8 G SYN CHOL* 1.3 G CHOL .20 G CHOL 0.65 G CHOL 50% .20 G 0.4 G CHOL .65 G *SYN CHOL = CHOLESTEROL SYNTHESIS

5 NORMAL CHOLESTEROL METABOLISMKey concepts: synthesis Primary synthetic sites are extrahepatic, but liver is key regulator of homeostasis Key concepts: absorption Largest source is biliary secretion, not diet. Normal absorption: 50% For cholesterol to be absorbed it must: undergo hydrolysis (de-esterification by esterases) be incorporated into micelles be taken up by cholesterol transporter be re-esterified and incorporated into chylomicrons

6 NORMAL CHOLESTEROL ABSORPTION1,300 mg/day 400 mg/day Oil phase

7 NORMAL CHOLESTEROL ABSORPTION1,300 mg/day 400 mg/day 17,400 mg/day Oil phase Plant sterols compete For cholesterol here

8 STRUCTURE OF PLANT STEROL ESTERSCholesterol Sitosterol HO HO O C - O Sitosterol Ester

9 NORMAL CHOLESTEROL ABSORPTION1,300 mg/day 400 mg/day 17,400 mg/day Oil phase 850 mg/day Ezetimibe competes For cholesterol here

10 NORMAL CHOLESTEROL ABSORPTION1,300 mg/day 400 mg/day 17,400 mg/day Oil phase 850 mg/day Defect in ABCG5/G8 transporter causes phytosterolemia

11 NORMAL CHOLESTEROL METABOLISMRole of Bile Salts, cholesterol, phospholipids in gall stone formation. Importance of Bile Salts for cholesterol absorption Key concepts: bile salt absorption inhibitors Bile acid binding compounds: Welchol (colesevelam hydrochloride) Cholestyramine Colestipol Fiber

12 Bile Acid Synthesis Cholesterol Cholic Acid Chenodeoxycholic AcidOH COOH COOH OH OH OH OH Cholic Acid Chenodeoxycholic Acid OH COOH COOH Deoxycholic Acid Lithocholic Acid OH OH

13 NORMAL CHOLESTEROL METABOLISMTissue pools 70G 0.85 G ABS CHOL 0.8 G SYN CHOL 1.3 G CHOL .20 G CHOL 0.65 G CHOL 50% .20 G 0.4 G CHOL .65 G

14 NORMAL CHOLESTEROL METABOLISMTissue pools 70G 0.85 G ABS CHOL 0.8 G SYN CHOL 0.35 G BA* 1.3 G CHOL 17.35 G BA* 17 G BA* .20 G CHOL 0.65 G CHOL 50% 95% .20 G 0.4 G CHOL .65 G .35 G 1.20 G CHOL + BA * BA = BILE ACIDS

15 NORMAL TRIGLYCERIDE METABOLISMKey concepts: absorption Triglyceride (i.e. energy) assimilation is key to the survival of the organism. Dietary triglyceride must be hydrolyzed to fatty acids, mono-glycerides and glycerol prior to absorption. Fatty acids must partition to micellar phase for absorption. For transport, triglyceride must be reconstituted from glycerol and fatty acid and incorporated into chylomicrons.

16 Structures of Fatty Acids16:0 (palmitic) HO O C cis-18:1 -6 (oleic) HO O trans-18:1 -6 (elaidic) C HO O C 18:2 -6 (linoleic) HO (alpha linolenic) O 18:3 -3 C HO O C 20:5 -3 (EPA) HO

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18 Fatty Acid and Triglyceride FluxACIDS (ALBUMIN) TG (VLDL) LIPO- PROTEIN LIPASE TG (CHYLO- MICRONS)

19 Dietary Carbohydrate Increases VLDL ProductionPlasma Triglyceride (VLDL) Dietary Carbohydrate

20 Lipoprotein Metabolism

21 Cholesterol Ester SynthesisAcyl-Cholesterol Acyl Transferase (ACAT) Cholesterol Cholesterol Ester COOH HO COO Lecithin-Cholesterol Acyl Transferase (LCAT) Lysolecithin COO COO COO COO + + N OPOO N OPOO

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26 Lipoproteins: Separation by – Electrophoresis Density Size by Electron Microscopy

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28 Pancreatic Lipase MovementMost pancreatic lipase is secreted into the pancreatic duct, but some moves back into capillaries.

29 Chylomicron Role in PancreatitisPancreatic lipase acts on chylomicrons adherent to capillary endothelium, producing fatty acid anions, or soaps. By detergent action, cell membranes are disrupted, releasing more lipase, and additional fatty acid anions are produced in a vicious cycle.

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34 Apolipoproteins B/E receptor ligand *E2:IDL; *E4: Diet ResponsivityapoE LpL inhibitor; antagonizes apoE apoC-III LpL activator apoC-II Inhibit Lp binding to LDL R; LCAT activator apoC-I apoB-48 Structural protein of all LP except HDL Binding to LDL receptor apoB-100 Tg metabolism; LCAT activator; diet response apoA-IV HL activation apoA-II HDL structural protein; LCAT activator;RCT apoA-I

35 Metabolic Relationships Among Lipoproteins1. VLDL LDL 2. 3. TG HDL Lipoprotein Lipase`

36  TRIGLYCERIDES SMALL DENSE LDL  HDL

37 Role of CETP in Triglyceride/ Cholesteryl Ester ExchangeVLDL LDL TG TG CETP HDL HDL CETP CE CE

38 UNINHIBITED LYPOLYSISDyslipidemia of Metabolic Syndrome UNINHIBITED LYPOLYSIS FREE FATTY ACIDS CETP TG CE CETP TG CE LIPASE VLDL sdLDL HDL LDL FATTY ACIDS GLYCEROL HDL CATABOLISM

39 Distribution of LDL Size Phenotypes According to Triglyceride LevelsCumulative percent of cases Phenotype A (light fluffy LDL) Phenotype B (small dense LDL) Austin et al, Circulation 1990; 82:495 Triglyceride (mg/dl)

40 Peroxisome Proliferator-Activated Receptor: A Nuclear Receptor for Metabolic Genesa, Basic mechanism of action of nuclear hormone receptors: bind to a specific sequence in the promoter of target genes (called hormone response elements), and activate transcription upon binding of ligand. Several nuclear hormone receptors, including the retinoic acid receptor, the vitamin D receptor and PPAR, can bind to DNA only as a heterodimer with the retinoid X receptor, RXR, as shown. b, some PPAR  and PPAR ligands. Kersten et al. Roles of PPARs in health and disease. Nature 2000; 405:

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42 Role of PPAR* and in VLDL, LDL and HDL metabolismTissues: Liver, kidney, heart, muscle. Ligands: fatty acids, fibrates Actions: Stimulate production of apo A I, lipoprotein lipase, increase expression of ABC A-1, increase FFA uptake and catabolism, decrease FFA and VLDL synthesis. PPAR Tissues: Adipose tissue and intestine. Ligands: arachidonic acid, Glitazones Actions: increase expression of ABC A-1, increase FFA synthesis and uptake by adipocytes, increase insulin sensitivity (?) * Peroxisome Proliferator Activated Receptor

43 HDL and Reverse Cholesterol Transport

44 HDL and Reverse Cholesterol TransportTangier Disease

45 HDL and Reverse Cholesterol Transport

46 HDL and Reverse Cholesterol Transport

47 HDL and Reverse Cholesterol Transport

48 HDL and Reverse Cholesterol TransportLDL-R

49 HDL and Reverse Cholesterol TransportLDL-R 50% of HDL C may Return to the liver On LDL via CETP

50 Lipoprotein(a), or Lp(a)An atherogenic lipoprotein containing apo(a) and apoB. 20-30% of people have levels suggesting C-V risk. Black subjects have Lp(a) normal range twice as high as white and Asiatic subjects. Apo(a) sequence similar to plasminogen, and Lp(a) interferes with spontaneous thrombolysis. Lp(a) levels highly genetic, resistant to diet and drug therapy, although niacin may help. Apo(a) “LDL” -S-S-

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