Lipid metabolism 2
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The bile salts such as cholic acid contain a hydrophobic side and a hydrophilic side, thus allowing bile salts to dissolve at an oil-water interface, with the hydrophobic surface in contact with the non-polar phase and the hydrophilic surface in the aqueous medium. This detergent action emulsifies fats and yields mixed micelles, which allow attack by water-soluble digestive enzymes and facilitate the absorption of lipids through the intestinal mucosa. Mixed Micelles also serve as transport vehicles for those lipids that are less water-soluble than fatty acids, such as cholesterol or the fat-soluble vitamins A, D, E, and K. Thus, efficient absorption of lipids depends on the presence of sufficient bile acids to solubilize the ingested lipids.
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Lipid metabolism 2
- 1. LIPID METABOLISM - Lipoprotein Metabolism
- 3. HMG 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. HMG-CoA reductase (3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, officially abbreviated HMGCR) is the rate-controlling enzyme (NADH-dependent, EC 1.1.1.88; NADPH- dependent, EC 1.1.1.34) of the mevalonate pathway, the metabolic pathway that produces Dolicho translatio proteins glycosyl dolichol phospha as a mem formatio oligosac GlcNAc glucose, GlcNAc acetylglu
- 4. NORMAL CHOLESTEROL METABOLISM Tissue pools 70G 0.8 G SYN CHOL* *SYN CHOL = CHOLESTEROL SYNTHESIS 0.4 G CHOL
- 5. NORMAL CHOLESTEROL METABOLISM Tissue pools 70G .65 G .20 G .20 G CHOL 0.65 G CHOL 0.85 G ABS CHOL 50% 0.4 G CHOL 0.8 G SYN CHOL* *SYN CHOL = CHOLESTEROL SYNTHESIS 1.3 G CHOL
- 6. Key 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 NORMAL CHOLESTEROL METABOLISM
- 7. 400 mg/day 1,300 mg/day NORMAL CHOLESTEROL ABSORPTION Oil phase
- 8. 400 mg/day 1,300 mg/day 17,400 mg/day NORMAL CHOLESTEROL ABSORPTION Plant sterols compete For cholesterol here Oil phase
- 9. STRUCTURE OF PLANT STEROL ESTERS HO Cholesterol Sitosterol HO O C - O Sitosterol Ester
- 10. 400 mg/day 1,300 mg/day 17,400 mg/day 850 mg/day NORMAL CHOLESTEROL ABSORPTION Ezetimibe competes For cholesterol here Oil phase Ezetimibe is used along with a low cholesterol/low fat diet and exercise to help lower cholesterol in the blood. Ezetimibe may be used alone or with other drugs (such as "statins" or fibrates). Ezetimibe works by reducing the amount of cholesterol your body absorbs from your diet.
- 11. 400 mg/day 1,300 mg/day 17,400 mg/day 850 mg/day NORMAL CHOLESTEROL ABSORPTION Defect in ABCG5/G8 transporter causes phytosterolemia Oil phase The sterol transporters ABCA1, ABCG5, and ABCG8 may play a role in the pathogenesis of human cholesterol related gallbladder diseases. ... Bile acids may promote an active conformation of purified ABCG5/G8 either by global stabilization of the transporter or by binding to a specific site on ABCG5/G8. This protein is a member of the White subfamily. The protein encoded by this gene functions as a half- transporter to limit intestinal absorption and promote biliary excretion of sterols. It is expressed in a tissue- specific manner in the liver, colon, and intestine.
- 12. Role of Bile Salts, cholesterol, phospholipids in gall stone formation. Importance of Bile Salts for cholesterol absorption NORMAL CHOLESTEROL METABOLISM Key concepts: bile salt absorption inhibitors – Bile acid binding compounds: • Welchol* • Cholestyramine • Colestipol • Fiber – Surgery: Partial ileal bypass. *Lowering cholesterol decreases the risk of heart disease and helps prevent strokes and heart attacks. Colesevelam is also used along with a proper diet and exercise to lower high blood sugar in people with type 2 diabetes.
- 13. Bile Acid Synthesis HO Cholesterol OH OH OH COOH OH OH COOH OH COOH OH OH COOH Chenodeoxycholic Acid Lithocholic Acid Cholic Acid Deoxycholic Acid
- 14. NORMAL CHOLESTEROL METABOLISM Tissue pools 70G 0.8 G SYN CHOL .65 G .20 G 0.85 G ABS CHOL 50% 0.4 G CHOL 1.3 G CHOL .20 G CHOL 0.65 G CHOL
- 15. 17 G BA* NORMAL CHOLESTEROL METABOLISM Tissue pools 70G 0.8 G SYN CHOL 17.35 G BA* 0.85 G ABS CHOL 0.35 G BA* .35 G .65 G .20 G 1.20 G CHOL + BA 50% 95% 0.4 G CHOL 1.3 G CHOL * BA = BILE ACIDS .20 G CHOL 0.65 G CHOL
- 16. Key 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. NORMAL TRIGLYCERIDE METABOLISM
- 17. Structures of Fatty Acids C HO O C HO O C HO O C HO O C HO O 18:0 cis-18:1 -6 trans-18:1 -6 18:2 -6 18:3 -3
- 18. Structures of Fatty Acids C HO O C HO O C HO O C HO O C HO O 16:0 (palmitic) cis-18:1 -6 (oleic) trans-18:1 -6 (elaidic 18:2 -6 (linoleic) 18:3 -3 (alpha linolenic) C HO O 20:5 -3 (EPA)
- 20. FATTY ACIDS (ALBUMIN) TG (VLDL) TG (CHYLO- MICRONS) LIPO- PROTEIN LIPASE Fatty Acid and Triglyceride Flux
- 21. Plasma Triglyceride (VLDL) Dietary Carbohydrate Increases VLDL Production Dietary Carbohydrate
- 22. Effect of Carbohydrate Restriction on Carbohydrate-induced Hypertriglyceridemia 0 500 1000 1500 2000 2500 3000 Initial Level End of Fast Inpatient Low CHO Diet Outpatient Low CHO Diet Reisell et al., Am J Clin Nutr 1966;19:84 Treatment: Fast for average 5 days, then consume low CHO diet. Composition of diet: 7-15% CHO 25-30% Prot 60-65% Fat
- 24. Cholesterol Ester Synthesis HO Cholesterol COOH COO COO OPOON+ Cholesterol Ester COO COO COO OPOON+ Lysolecithin Lecithin-Cholesterol Acyl Transferase (LCAT) Acyl-Cholesterol Acyl Transferase (ACAT)
- 29. Lipoproteins: Separation by – Electrophoresis Density Size by Electron Microscopy
- 32. Pancreatic Lipase Movement Most pancreatic lipase is secreted into the pancreatic duct, but some moves back into capillaries.
- 33. Chylomicron Role in Pancreatitis Pancreatic 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.
- 34. IDL is one of the five major groups of lipoproteins (Chylomicrons, VLDL, IDL, LDL, HDL) that enable fats and cholesterol to move within the water-based solution of the bloodstream. ... VLDL is a large, triglyceride-rich lipoprotein secreted by the liver that transports triglyceride to adipose tissue and muscle.
- 38. Apolipoproteins B/E receptor ligand *E2:IDL; *E4: Diet ResponsivityapoE LpL inhibitor; antagonizes apoEapoC-III LpL activatorapoC-II Inhibit Lp binding to LDL R; LCAT activatorapoC-I apoB-48 Structural protein of all LP except HDL Binding to LDL receptor apoB-100 Tg metabolism; LCAT activator; diet responseapoA-IV HL activationapoA-II HDL structural protein; LCAT activator;RCTapoA-I Apolipoproteins are proteins that bind lipids (oil-soluble substances such as fat and cholesterol) to form lipoproteins. They transport the lipids through the lymphatic and circulatory systems. The lipid components of lipoproteins are insoluble in water. Lecithin–cholesterol acyltransferase (LCAT, also called phosphatidylcholine–sterol O-acyltransferase) is an enzyme that converts free cholesterol into cholesteryl ester (a more hydrophobic form of cholesterol), which is then sequestered into the core of a lipoprotein particle, eventually making the newly synthesized HDL spherical and forcing the reaction to become unidirectional since the particles are removed from the surface. The enzyme is bound to high-density lipoproteins (HDLs) and low-density lipoproteins in the blood plasma.[5] LCAT deficiencycan cause impaired vision due to cholesterol corneal opacities, anemia, and kidney damage.
- 41. Role of CETP in Triglyceride/ Cholesteryl Ester Exchange VLDL CETP HDL TG CE LDLCETPHDL TG CE Cholesteryl ester transfer protein (CETP), also called plasma lipid transfer protein, is a plasma protein that facilitates the transport of cholesteryl esters and triglycerides between the lipoproteins.
- 42. Role of Triglycerides in Producing Small Dense LDL or HDL TG TG TG CE CE CE CETP Lipase 1. CE exchanged for TG 2. TG removed
- 43. FREE FATTY ACIDS Dyslipidemia of Metabolic Syndrome VLDL CETP TG CE HDL LDL CETP TG CE LIPASE sdLDL FATTY ACIDS GLYCEROL HDL CATABOLISM UNINHIBITED LYPOLYSIS Low- density lipoprotein (LDL ) plays a key role in the development and progression of atherosclerosis & cardiovascular disease. ... Modified sdLDL is a potent inductor of inflammatory processes associated with cardiovascular disease.
- 44. Distribution of LDL Size Phenotypes According to Triglyceride Levels 0 10 20 30 40 50 60 70 80 90 100 0 50 100 150 200 250 300 Phenotype A (light fluffy LDL) Phenotype B (small dense LDL) Cumulativepercentofcases Triglyceride (mg/dl) Austin et al, Circulation 1990; 82:495
- 45. Peroxisome Proliferator-Activated Receptor: A Nuclear Receptor for Metabolic Genes a, 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: 421-424
- 46. Role of PPAR* and in VLDL, LDL and HDL metabolism * Peroxisome Proliferator Activated Receptor PPAR Tissues: 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 (?)
- 47. HDL and Reverse Cholesterol Transport
- 48. HDL and Reverse Cholesterol Transport Tangier Disease Tangier disease is an inherited disorder characterized by significantly reduced levels of high-density lipoprotein (HDL) in the blood. HDL transports cholesterol and certain fats called phospholipids from the body's tissues to the liver, where they are removed from the blood.
- 49. HDL and Reverse Cholesterol Transport
- 50. HDL and Reverse Cholesterol Transport
- 51. HDL and Reverse Cholesterol Transport
- 52. LDL-R HDL and Reverse Cholesterol Transport
- 53. LDL-R 50% of HDL C may Return to the liver On LDL via CETP HDL and Reverse Cholesterol Transport
- 54. • 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. “LDL” Apo(a) -S-S- Lipoprotein(a), or Lp(a)
- 57. Summary – Lipid and Lipoprotein Metabolism • Cholesterol absorption, synthesis, and disposition • Triglyceride/fatty acid transformations and energy metabolism • Lipoprotein core and surface components • Lipoprotein origins and destinations governed by apo’s • Derangement in the metabolic syndrome • Reverse cholesterol transport – the dominant direction • Lipoprotein(a) • Lipoproteins in the arterial wall