CVS lipoprotein metabolism, .pptx
Download as PPTX, PDF
0 likes130 views
Lipoproteins are complexes of protein and lipids that transport lipids in the bloodstream. There are four main types of lipoproteins: chylomicrons, very low-density lipoproteins (VLDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). Each type has a specific function in lipid transport and metabolism. Chylomicrons transport dietary lipids from the intestine to other tissues, VLDL transports endogenous lipids from the liver, LDL delivers cholesterol to tissues, and HDL transports cholesterol from tissues back to the liver. The apolipoproteins associated with each lipoprotein complex help determine its structure and function in lipid transport and metabolism.
CVS lipoprotein metabolism, .pptx
- 1. Lipoproteins and their metabolism By Don. Siyum A.
- 2. Complex between protein and lipid, are of two types Structural lipoproteins Present in cellular and subcellular membranes widely distributed in tissues Lung surfactant (lecithin protein complex) Rhodopsin of rods Transport lipoproteins Present in blood plasma Apo(lipo)protein + lipid (C, CE, PL & TG). Lipoproteins
- 4. Lipoproteins and Lipid transport Why lipoproteins required? Lipids are insoluble in plasma Types of lipoproteins- 4 major types Chylomicrons Very Low-Density Lipoproteins (VLDL) Low- Density Lipoproteins (LDL) High Density Lipoproteins (HDL) How we distinguish lipoproteins from each other? Density , Lipid and protein composition , Role in lipid transport 4
- 5. Fig: Electrophoresis pattern of plasma lipoprotein
- 6. Composition and Properties of Human Lipoproteins
- 8. Chylomicrons VLDL LDL HDL Albumin-FFAs complex Source Intestine Liver/intestine VLDL Liver/intestine Liver-Adipose tissue Electrophoretic band Origin Pre-硫 硫 留 Plasma albumin Diameter (nm) 75 1200 30-80 18-25 9-12 (HDL2); 5- (HDL3) - Density (g/mL) 0.93 0.93-1.006 1.019-1.063 1.063-1.125(HDL2); 1,125-1.21(HDL3) >1.281 Apoproteins ApoB48; CI, II, and III; AI, II and IV; E ApoB100; CI, II and III; E ApoB100, CI, II and III, E ApoAI, II, IV; CI, II and III; E - % Protein 1.0 2.0 7.0 10.0 21.0 33 57 99 % Triglycerides 80-95 55-80 5-15 5-10 0 % Phospholipids 3-9 10-20 20-25 20-30 0 % Cholesterol esters 2-7 5-15 40-50 15-25 0 FFAs 0 1 1 0 (HDL2); 6(HDL3) 100
- 9. Function of lipoproteins Transport of Exogenous Lipids Chylomicrons Transport of Endogenous Lipids VLDL, LDL, HDL
- 11. Structural stability to the lipoproteins, e.g. Apo-B-integral proteins As ligands for lipoprotein-receptor apo B-100 and apo E for the LDL receptor, apo E for LDL receptor-related protein (LRP) (for chylomicron remnant) apo A-I for the HDL receptor. As enzyme cofactors regulating LP metabolism apo-CII for lipoprotein lipase (LPL) apo A-I for lecithin:cholesterol acyltransferase (LCAT) As enzyme inhibitors apo A-II and apo C-III are inhibitors for LPL apo C-I for cholesteryl ester transfer protein (CETP) Function of apoproteins/ apolipoproteins/
- 14. A. Chylomicrons Source & fate of exogenous lipids Source: dietary lipids (TG, Cholesterol,phospholipids, CE) Cholesterol: Intestinal cholesterol and plant sterol absorption is mediated by Niemann- Pick C1-like 1 protein (NPC1L1) Dietary cholesterol is esterified by the type 2 isozymes of acyl coenzyme A:cholesterol acyltransferase (ACAT) Plant sterols are not esterified and incorporated into chylomicrons Plant sterols returned to intestinal lumen via two ATP- binding cassette (ABC) half-transporters,
- 15. Absorption of cholesterol and export in to blood
- 17. Dietary Triacylglycerol (TG) Re-esterification of TG in ER is regulated by diacylglycerol transferase TGs are transferred by microsomal TG transfer protein (MTP) to the site of synthesized apoB-48 Formation of Nascent Chylomicron by intestinal epithelial cells Assembly of chylomicron with addition of apoB-48, apoA-I, apoA-IV, and some C & E Maturation of Chylomicron in plasma Acquire apoprotein from HDL in plasma: apoE and apoC-I, C-II, and C-III The apparent molecular wt of apoB-48 is 48% that of apoB-100.
- 21. Overview of the formation of triglyceride deposits in the adipose tissue .
- 22. Metabolism of Circulating Chylomicron Removal of TG tissues capillaries luminal surface have anchored LPL mainly adipose tissue, skeletal and cardiac muscle(for 80% of TG), spleen, lung, renal medulla, aorta, diaphragm and breast tissue of lactating women. Liver capillaries : hepatic lipase In adipose tissue (but not in muscle), insulin stimulates lipoprotein lipase synthesis insulin resistance are often associated with an increased concentration of total plasma triglycerides
- 23. About LPL Adipose tissue LPL has high Km, (cardiac) muscle has lower Km ApoC-II & phospholipids are activator cofactors for LPL. Loss of 90% of the chylomicron TG and apo C (which returns to HDL) while apo E is retained.
- 24. Remnant attachment (lack 90% TG and apo C II)to liver (aided by Apo E) & processed by Hepatic lipase apo-E mediates remnant uptake by interacting with the hepatic LDL receptor or LRP. Apo protein , TG ,CE and phospholipids= Hydrolyzing in lysosome LRP is the back-up receptor responsible for the uptake of apoE-enriched remnant of chylomicron (similar for LDL) Blood normally contains no chylomicrons after a 12-hour fast uptake of Chylomicron Remnants
- 25. What will happen if an individual is LPL deficient ? What will happen if an individual is an apo CII deficient ? Hypertriglycerolemma
- 26. Summary: Metabolic fate of chylomicrons HL=Hepatic Lipase; LRP, LDL receptor-related protein High affinity of the muscle LPL permits to use Fatty acids of VLDL & Chylomicron * Low affinity of Adipose LPL. So, lipid storage is during meal 26
- 27. Hypertriglyceridemia abnormally high quantity of chylomicrons, VLDL, or both. plasma triglycerides in the fasting state: >150 mg/dL (1.7 mM). Severe hypertriglyceridemia: > 1,000 mg/dL (>11 mM) VLDL is formed at an excessive rate, or chylomicrons and VLDL are removed at an abnormally low rate
- 28. Hypertriglyceridemia increases risk of cardiovascular disease (mechanism unknown) major risk of very severe hypertriglyceridemia is pancreatitis and tuberous xanthomas Factors insulin resistance (as in all obese and most type 2 diabetic patients), hypothyroidism, excessive alcohol intake, certain medications, pregnancy, and genetic predisposition (lipoprotein lipase, apolipoprotein C-II, or apolipoprotein E)
- 29. Reading Assignment Association of the following with reduction of hypertriglyceridemia Life style Statin Fibrate drugs Fish oil (-3 fatty acids) Nicotinic acid (niacin)
- 30. B. Very-Low-Density Lipoproteins (VLDL) Source: The liver main fats:- triglycerides , cholesterol and cholesteryl esters Factors Increasing Liver Lipogenesis (TG & VLDL) (1) the fed state (2) diets high in carbohydrate (3) high levels of circulating free fatty acids (4) ingestion of ethanol (5) presence of high concentrations of insulin
- 31. Fig: Synthesis and assembly of Lipoprotein in liver cells.
- 33. Sources of VLDL apoproteins Liver (constitutive): ApoB-100, also apoE, and apo C-I & C- III ( TAG transfer protein) Plasma HDL: Most of the apoE & ApoC II Metabolism of VLDL LPL in capillaries of muscle and adipose tissue depletes TAG TAG transfer to HDL and Cholesterol from HDL to VLDL (CE transfer protein) decreased in size and increase in density = converted to IDL
- 34. Fate of IDL 40% - 60% of IDL cleared from plasma by the liver LDL receptors and LRP recognizing apoB-100 & apo-E (Apo C is returned to HDL) Depending on their need or cholesterol, hepatocytes and peripheral cells display LDL receptors on their surface LRP is enhanced by insulin & is abundant on liver, brain, and placenta LRP not significantly affected by intracellular cholesterol concentration IDL is converted to LDL by removal of TGs (hepatic lipase) The apo E redistribute to HDL.
- 35. Ratio of triglyceride/cholesterol by weight VLDL 5 : 1 IDL 1 : 1 LDL 1 : 10
- 36. C. Low-Density Lipoprotein (LDL) The most important function of LDL is to supply cholesterol to the extrahepatic tissue ApoB-100 is the ligand that binds LDL to its receptor Thyroxine and estrogen enhance LDL receptor gene expression, lowering LDL-cholesterol. liver secretes the enzyme Proprotein convertase
- 37. Fig: Endocytosis and degradation of lipoprotein particles. FIG : The structure of the LDL receptor.
- 38. Deficiency of LDL receptors: A defect in LDL receptors results in the elevation of plasma LDL-C Deficiency of LDL receptors is observed in type IIa hyperbetalipoproteinemia. This disorder is associated with a very high risk of atherosclerosi s(particuIarly of coronary artery).
- 39. About 3% of Caucasians are heterozygous for a loss-of - function mutation in the PCSK9 gene and have better survival of LDL receptors and about a 15% reduction in LDL cholesterol. Gain-of - function mutations in PCSK9 are uncommon and lead to hypercholesterolemia
- 40. D. High-Density Lipoproteins (HDL) Synthesized by the liver and intestine pre硫-HDL:- Small-sized & contains phospholipids, free cholesterol, and a variety of apolipoproteins, predominantly apoA-I, apoA-II, apoC-I, and apoC-II. Contain very low levels of TGs or cholesterol esters Nascent HDL (Discoid) HDL 3 rich in A-I and apo A-II, (spherical) HDL2 rich in Apo E (round) Export of Cholesterol From Peripheral Cells (Reverse Cholesterol Transport)
- 42. Lecithin: Cholesterolacyl Transferase (LCAT) bind to the disk from the circulation (activated by apo AI) LCAT convert the surface phospholipid and free cholesterol into lysolecithin (which then bind to plasma albumin) and Cholesterol ester VLDL exchange lipids with HDL (cholesteryl ester transfer protein (CETP) ).This is why low HDL observed in hypertriglyceridemia. HDL off load some of their CE in the liver and in steroidogenic organs (SCARB1, SRB1, SRBI) equilibrate CE in HDL with cellular CE
- 44. HDL is a reservoir of apolipoproteins: HDL particles serve as a circulating reservoir of apo C II (an activator of lipoprotein lipase), and apo E ( required for the receptor-mediated endocytosis of chylomicron remnants)
- 46. Definition: Elevation of plasma cholesterol or LDL cholesterol and/or triacylglycerol Accompanied by low HDL level that contributes to the development of atherosclerosis. Causes: Primary (genetic) disorder / Secondary to a metabolic disease or condition. Primary genetic dyslipidemias, hyperlipidemia Single or multiple genetic mutations that results in - Overproduction or defective clearance of TGs and LDL cholesterol - Underproduction or excessive clearance of HDL. Overview of Hyperlipidemias (Dyslipidemias)
- 47. Abetalipoproteinemia autosomal recessively inherited disorder characterized by an absence of lipoprotein particles that carry apoprotein B-48 or B-100 ( chylomicrons, VLDL, IDL, and LDL). The disease is due to a deficiency of MTP. Familial hypobetalipoproteinemia is caused by heterozygosity of truncated apolipoprotein B. Patients develop a fatty liver due to reduced export of triglycerides. CETP defect: hypertriglyceridemia with HDL cholesterol levels below 20 mg/ dL (0.5 mM). a deficiency of functional apolipoprotein A-I, ABCA1, or LCAT :- Patients have HDL cholesterol levels lower than 20 mg/ dL (0.5 mM) without marked hypertriglyceridemia may have.
- 48. Familial hypercholesterolemia Secondary dyslipidemias : occur mainly in adults. Sedentary lifestyle, age, Excessive dietary saturated fat , cholesterol, and trans-fatty acids, disease, e.g., Diabetes mellitus, Alcoholism, Endocrine abnormality e.g Hypothyroidism, Primary biliary cirrhosis, Other cholestatic liver diseases, Use of drugs that perturb LP formation or catabolism Hyperlipidemia is a major cause of atherosclerosis E.g. Coronary heart disease (CHD)
- 49. Laboratory measurement of Cholesterol Clinical laboratories routinely measure total cholesterol, HDL cholesterol, and triglycerides in plasma samples LDL cholesterol is usually calculated (Friedewald equation) LDL cholesterol = total cholesterol HDL cholesterol (total triglycerides/5) If all concentrations are in mg/dLI the TG correction factor is 0.2 ;if all concentrations are calculated in units of mM,
- 50. Reference Harpers Illustrated Biochemistry Marks medical Biochemistry Lippincot Illustrated Biochemistry
Editor's Notes
- #23: Obesity and insulin resistance are o en associated with an increased concentration o total plasma triglycerides.