Lipoprotein Metabolism Lecture Notes PDF

Metabolism and role of lipoproteins  Metabolism of Lipoproteins Exogeno Endogeno us us pathwa pathwa y y Chylomicr VLDL(LDL)& ons HDL (Liver (Intestinal...

Metabolism and role of lipoproteins  Metabolism of Lipoproteins Exogeno Endogeno us us pathwa pathwa y y Chylomicr VLDL(LDL)& ons HDL (Liver (Intestinal Lipoprotei 9  Absorption of Lipids Glycerol, short chain FA & medium chain FA are directly absorbed from the intestinal lumen → portal vein → liver Long-chain fatty acids, free cholesterol and β-acyl glycerol form mixed micelles with bile salts  Micelles Spherical Clusters of amphipathic lipids hydrophobic groups on the inside hydrophilic groups on the outside of clusters Mixed micelles : soluble in the aqueous environment of the intestinal lumen Approach the brush border membrane of the enterocytes The micelles are absorbed by the enterocytes of the small intestine through endocytosis. In enterocytes takes place resynthesis of TAG from monoglycerides and FA of micelles. Resynthesized TAG are incorporated into chylomicrons.  Metabolism of chylomicrons ❑Chylomicrons are found in chyle formed only by the lymphatic system draining the intestine. ❑They are responsible for the transport of all dietary lipids into the circulation. Synthesis of Chylomicrons 1) Synthesis of Apo B48 2) Synthesis of ApoB100 Metabolism of chylomicrons ❑Apolipoprotein B, synthesized in the RER, is incorporated into lipoproteins in the SER, the main site of synthesis of triacylglycerol. ❑After addition of carbohydrate residues, they are released from the cell by reverse pinocytosis. ❑Chylomicrons pass into the lymphatic system. Clinical Significance- In Abetalipoproteinemia (a rare disease), lipoproteins containing apo B are not formed and lipid droplets accumulate in the intestine and liver  Synthesis of Chylomicrons o Synthesis of lipids and formation of lipoprotein: long-chain fatty acids are esterified to yield to triacylglycerol in the mucosal cells and together with the other products of lipid digestion, are incorporated into lipoproteins in the SER, the main site of synthesis of triacylglycerol. o Addition of Carbohydrate: carbohydrate residues are added in the golgi apparatus. o Release of Chylomicrons: after addition of carbohydrate residues in Golgi apparatus, they are released from the cell by reverse pinocytosis. o Transportation: chylomicrons pass into the lymphatic system and eventually enter the systemic circulation.  Catabolism of Chylomicrons The enzyme lipoprotein lipase acts upon chylomicrons. Reaction with lipoprotein lipase results in the loss of approximately 90% of the triacylglycerol of chylomicrons. The resulting chylomicron remnant is about half the diameter of the parent chylomicron and is relatively enriched in cholesterol and cholesteryl esters because of the loss of triacylglycerol.  Catabolism of Chylomicrons Chylomicron remnants are taken up by the liver by receptor- mediated endocytosis, and the cholesteryl esters and triacylglycerols are hydrolyzed and metabolized. Hepatic lipase has a dual role: (1) it acts as a ligand to facilitate remnant uptake and (2) it hydrolyzes remnant triacylglycerol and phospholipid. The products released are re-utilized for the synthesis of VLDL. Catabolism of Chylomicrons Lipoproteins Lipoproteins consist of a nonpolar core and a single surface layer of amphipathic lipids The nonpolar lipid core consists of mainly triacylglycerol and cholesteryl ester and is surrounded by a single surface layer of amphipathic phospholipid and cholesterol molecules  Classification of Lipoproteins based on density Lipoproteins may be classified according to their density: Chylomicrons Very-low-density lipoproteins (VLDL), Intermediate-density lipoproteins (IDL), Low-density lipoproteins (LDL) High-density lipoproteins (HDL)  Classification of Lipoproteins based on electrophoretic pattern Lipoproteins may also be separated by electrophoresis into : Beta (LDL), Prebeta (VLDL), Broad beta (IDL)and Alpha (HDL) lipoproteins.  Classification of Lipoproteins Based on nature of Apoprotein content ❑One or more apolipoproteins (proteins or polypeptides) are present in each lipoprotein. ❑The major apolipoproteins of HDL (α- lipoprotein) are designated A. ❑The main apolipoprotein of LDL (β -lipoprotein) is apolipoprotein B (B-100), which is found also in VLDL. ❑Chylomicons contain a truncated form of apo B (B-48) that is synthesized in the intestine, while B-100 is synthesized in the liver. ❑Apo E is found in VLDL, HDL, Chylomicons, and chylomicron remnants.  Functions of Apo proteins (1)They can form part of the structure of the lipoprotein, e.g. apo B, structural component of VLDL and Chylomicons (2)They are enzyme cofactors, e.g. C-II for lipoprotein lipase, A-I for lecithin: cholesterol acyl transferase (LCAT), or enzyme inhibitors, eg, apo A-II and apo C-III for lipoprotein lipase, apo C-I for cholesteryl ester transfer protein (3)They act as ligands for interaction with lipoprotein receptors in tissues, e.g. apo B-100 and apo E for the LDL receptor, apo A-I for the HDL receptor.  Metabolism of lipoproteins VLDL VLDL LDL Cappilar Cell Receptor terol oles ch HDL Cholesterol rol ste Excess ole ch duodenum Synthesis  Metabolism of VLDL There are striking similarities in the mechanisms of formation of chylomicrons by intestinal cells and of VLDL by hepatic parenchymal cells. Apart from the mammary gland, the intestine and liver are the only tissues from which particulate lipid is secreted. Newly secreted or "nascent" VLDL contain only a small amount of apolipoproteins C and E. Apo B 100 is essential for VLDL formation.  Metabolism of VLDL Catabolism of VLDL is like chylomicrons Hydrolysis takes place while the VLDLs are attached to the enzyme on the endothelium. Triacylglycerol is hydrolyzed progressively through a diacyl glycerol to a monoacylglycerol and finally to free fatty acids plus glycerol. Some of the released free fatty acids return to the circulation, attached to albumin, but the bulk is transported into the tissue. Reaction with lipoprotein lipase results in the loss of approximately 90% of the triacylglycerol of VLDLs and in the loss of apo C. These changes occurring to VLDL, lead to the formation of VLDL remnants or IDL (intermediate-density lipoprotein) In humans, a relatively large proportion of IDL forms LDL, accounting for the increased concentrations of LDL in humans compared with  Metabolism of LDL The liver and many extra hepatic tissues express the LDL (apo B-100, E) receptor. This receptor is defective in familial hypercholesterolemia. Approximately 30% of LDL is degraded in extra-hepatic tissues and 70% in the liver. A positive correlation exists between the incidence of coronary atherosclerosis and the plasma concentration of LDL cholesterol.  Metabolism of HDL Synthesis of HDL HDL is synthesized and secreted from both liver and intestine. However, apo C and apo E are synthesized in the liver and transferred from liver HDL to intestinal HDL when the latter enters the plasma. The nonpolar cholesteryl esters move into the hydrophobic interior of the bilayer. Thus, a nonpolar core is generated, forming a spherical, pseudomicellar HDL covered by a surface film of polar lipids and apolipoproteins. This aids the removal of excess unesterified cholesterol from lipoproteins and tissues.  Functions of HDL Scavenging action - HDL scavenges extra cholesterol from peripheral tissues by reverse cholesterol transport. HDL, with the help of apo E competes with LDL for binding sites on the membranes and prevents internalization of LDL cholesterol in the smooth cells of the arterial walls. HDL contributes its apo C and E to nascent VLDL and chylomicrons for receptor-mediated endocytosis. HDL stimulated prostacyclin synthesis by the endothelial cells, which prevents thrombus formation. Summary of formation and fate of lipoproteins ❑Chylomicrons is a transporter of dietary lipids whereas VLDL is a transporter of endogenous lipids(mainly TGs). ❑LDL transports cholesterol to peripheral cells while HDL transports cholesterol from peripheral cells back to liver.  Hyperlipidemia (hyperlipoproteinemia) Hyperlipoproteinemia is a metabolic disorder characterized by abnormally elevated concentrations of specific lipoprotein particles in the plasma. Hyperlipidemia (i.e., elevated plasma cholesterol or triglyceride levels or both) is present in all hyperlipoproteinemia. Primary disorders Alterations in lipoproteins result from genetic mutations  Secondary disorders Alterations in lipoproteins occur from some other underlying systemic disorder, such as: - pregnancy, - hypothyroidism, - cholestasis, - diabetes mellitus, -pancreatitis, -gout, -type I glycogen storage disease. Primary Disorders of Plasma Lipoproteins (Dyslipoproteinemias) ❑Inherited defects in lipoprotein metabolism All to the primary condition of either hypo- or hyperlipoproteinemia. ❑All the primary conditions are due to a defect at a stage in lipoprotein formation, transport, or  Primary Disorders of Plasma Lipoproteins (Dyslipoproteinemias) Name Defect Characteristics Hypolipoproteinemias Abetalipoproteinemia No chylomicrons, VLDL, or Rare, blood acylglycerols LDL are formed because of low; intestine and liver defect in the loading of apo accumulate acylglycerols. B with lipid. Intestinal malabsorption. Familial alpha-lipoprotein All have low or near absence Hypertriacylglycerolemia deficiency of HDL. due to absence of apo C-II, Tangier disease Low LDL levels. Atherosclerosis in the Fish-eye disease elderly. Apo-A-I deficiencies 28  Primary Disorders of Plasma Lipoproteins (Dyslipoproteinemias) Name Defect Characteristics Hyperlipoproteinemia Familial lipoprotein lipase Hypertriacylglycerolemia due Slow clearance of deficiency (type I) to deficiency of LPL, chylomicrons and VLDL. Low abnormal LPL, or apo C-II levels of LDL and HDL. No deficiency causing inactive increased risk of coronary LPL. disease. Familial Defective LDL receptors or Elevated LDL levels and hypercholesterolemia mutation hypercholesterolemia, (type in ligand region of apo B-100. resulting in atherosclerosis II a) and coronary disease. 29  Primary Disorders of Plasma Lipoproteins (Dyslipoproteinemias) Name Defect Characteristics Familial type III Deficiency in remnant Increase in chylomicron and hyperlipoproteinemia clearance by the liver is due VLDL remnants , Causes (broad beta disease, to abnormality in apo E. hypercholesterolemia, remnant removal disease, xanthomas, and familial atherosclerosis. dysbetalipoproteinemia) Familial Overproduction of VLDL High cholesterol, VLDL, Hypertriacylglycerolemia often associated with Subnormal LDL and HDL. (type IV) glucose intolerance and Associated with Alcoholism, hyperinsulinemia. diabetes mellitus and obesity. Hepatic lipase deficiency Deficiency of the enzyme Patients have xanthomas and leads to accumulation of coronary heart disease. large triacylglycerol-rich HDL and VLDL remnants  Atheroscleros is ❑Atherosclerosis is a disease of large and medium-sized muscular arteries and is characterized by the buildup of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall- atheroma (also called atheromatous or atherosclerotic 5 plaques),protrude into 5 Serum lipids - desirable, borderline risk, and high risk levels of Total atherosclerosis HDL LDL Trigly- cholesterol cholesterol cholesterol cerides (mg/dl) (mg/dl) (mg/dl) (mg/dl) Desirable 60 (females)