Lipoprotein 3x PDF

Which fatty acids are generally transported with Albumin? FATS CANNOT DISSOLVE IN THE BLOOD: ’ Free (nonesterified) short- and medium-chain fatty acids are transported in the blood bound to ALBUMIN ’ Other lipids are transported in the blood as part of LIPOPROTEINS...

Which fatty acids are generally transported with Albumin? FATS CANNOT DISSOLVE IN THE BLOOD: ’ Free (nonesterified) short- and medium-chain fatty acids are transported in the blood bound to ALBUMIN ’ Other lipids are transported in the blood as part of LIPOPROTEINS LIPOPROTEIN : PROTEINS + LIPIDS LIPOPROTEINS HYDROPHILIC EXTERNAL SURFACE ’ Free cholesterol ’ Phospholipids ’ Apolipoproteins HYDROPHOBIC CORE ’ Cholesterol esters ’ Triacylglycerols LIPOPROTEINS LIPOPROTEINS HAVE DIFFERENT SIZE AND DENSITY LIPOPROTEINS  Chylomicrons  Very low-density lipoproteins (VLDL)  Remnant particles (include IDL)  Low-density lipoproteins (LDL)  High-density lipoproteins (HDL) LIPOPROTEINS Lipoproteins are classified on the basis of their properties Lipoprotein Density Diameter Protein Phospholipid Triacylglycerol class (g/mL) (nm) % of dry wt % % of dry wt HDL 1.21 - 1.063 5 – 15 33 29 8 LDL 1.063 - 1.019 18 – 28 25 21 4 IDL 1.019 - 1.006 25 – 50 18 22 31 VLDL 1.006 - 0.95 30 – 80 10 18 50 chylomicrons < 0.95 100 – 500 1-2 7 84 LIPOPROTEINS ’ Chylomicron ’ VLDL triacylglycerol rich ’ LDL ’ HDL cholesterol rich LIPOPROTEINS CENTRIFUGATION Lipoproteins with high lipid content: ’ have low density ’ have larger size ’ float on centrifugation Lipoproteins with high protein content: ’ have high density ’ have compact size ’ sediment easily LIPOPROTEINS ELEKTROPHORESIS ’ Chylomicrons (Fed state) (0%) ’  lipoprotein (LDL) (45-70%) ’ pre  lipoprotein (VLDL) (12-30%) ’  lipoprotein (HDL) (20-48%) HDL moves the fasted (The mobility of a lipoprotein is mainly dependent upon protein content: among the lipoprotein due to its high protein content. Those with higher protein content will move faster towards) True Apolipoproteins PROTEIN COMPONENTS OF LIPOPROTEIN PARTICLES why can we transfere apoc from HDL to VLDL but not apo b ApoB can be easily seprated from LDL during reaction. False ’ Some of them are embedded in the particle surface (apoB) (cannot be removed) ’ Some of them are only loosely bound (apoC) (can be freely transferred to other lipoproteins) Apolipoproteins Apolipoproteins ROLES:  determine lipoproteins metabolic fate through interactions with cellular receptors.  activators and inhibitors of enzymes in lipoprotein metabolism Apolipoproteins Apo AI  synthesized in the liver and intestine  major protein component of HDL With up regulation of which one  ligand for HDL receptor of the APO1 which one of the receptors below will up regulate (plays a role in the interaction of HDL with ABCA1, ABCG1, SR-B1) as well ?  Activator of lecithin cholesterolacyltransferase (LCAT) (High levels of Apo A-I is associated with a decreased risk of atherosclerosis) Apolipoproteins Apo AII  protein component of HDL  Inhibitor for lipoprotein lipoprotein lipase  a strong predictor of risk for CVD Which one the APO proteins work in opposition ? Apolipoproteins In which one the lipoproteins below Apo b 100 can not be found Apo B100  synthesized in the liver  major structural component of VLDL, IDL, and LDL.  controls the metabolism of LDL  ligand for LDL (apoB/E) receptor (has a role in the clearance of lipoprotein particles)  High levels of Apo B- 100 is associated with an increased risk of atherosclerosis. Apolipoproteins Apo B48 :  synthesized in the intestine  truncated form of apoB100  controls the metabolism of chylomicrons  is not recognized by the LDL receptor. Apolipoproteins Apo CI  inhibitor for cholesteryl ester transfer protein Apo CII  activator of lipoprotein lipase Apo CIII  inhibitor for lipoprotein lipase Apolipoproteins Apo E  found in VLDL, HDL, chylomicrons and chylomicron remnants  controls the receptor binding of remnant particles  ligand for LDL (apoB/E) receptor Apolipoproteins Apolipoprotein (a) :  synthesized in the liver.  a component of lipoprotein(a)  attached to Apo B-100 via a disulfide bond.  inhibitor of fibrinolysis  enhance the uptake of lipoproteins by macrophages  = High levels of Apo (a) are associated with an increased risk of Apo A is associated with increased ridk of atherosclerosis. atherosclerosis unlike ApoA1 due to its ability ro inhabit fibrinolysis Lipoprotein Receptors  LDL receptor.  Scavenger receptor Both types of the receptors span cell membranes. Lipoprotein Receptors LDL receptor (apoB/E receptor) ’ Joseph Goldstein and Michael Brown ’ 1985 Nobel Prize Lipoprotein Receptors LDL receptor takes up chylomicrons by ApoE not apo B48. False Just like scavenger receptors LDL receptors are unregulated. False LDL receptor (apoB/E receptor)  present in the liver and most other tissues  has well-defined ligands  recognizes apoB100 and apoE (not apoB48) (= mediates the uptake of LDL, chylomicron remnants, IDL,  is regulated by the intracellular cholesterol concentration the action of lipoprotein recpters are requlated by which one of the fallowing Lipoprotein Receptors apoE of chylomicron remnants can bind to ’ apoB/E receptor ’ LDL receptor-related protein (LRP) Lipoprotein Receptors LDL receptor-related protein (LRP) ’ a member of the LDL receptor family. ’ expressed in multiple tissues (liver etc.) ’ recognizes Apo E ’ mediates the uptake of chylomicron remnants and IDL. Lipoprotein Receptors Scavenger receptor  Present on cell membranes  Nonspecific and nonregulated  can bind many different molecules  bind chemically modified (e.g. oxidized) LDL  present on phagocytic cells (macrophages)  not subject to feedback regulation Lipoprotein Receptors Class B Scavenger Receptor B1 (SR-B1) ’ expressed in the liver, adrenal glands, ovaries, testes, macrophages, and other cells. In the liver and steroid producing cells; ’ mediates the selective uptake of cholesterol esters from HDL particles. In macrophages and other cells; ’ facilitates the efflux of cholesterol from the cell to HDL particles. Lipoprotein Receptors ATP-Binding Cassette Transporter A1 (ABCA1) ’ expressed in many cells including hepatocytes, enterocytes, and macrophages. ’ mediates the transport of cholesterol and phospholipids from the cell to pre-beta-HDL Lipoprotein Receptors ATP-Binding Cassette Transporter G1 (ABCG1) ’ expressed in many different cell types ’ mediates the efflux of cholesterol from the cell to HDL particles. Lipoprotein Receptors ATP-Binding Cassette Transporter G5 and G8 (ABCG5/ABCG8) ’ expressed in the liver and intestine In the intestine; ’ mediate the movement of plant sterols and cholesterol from inside the enterocyte into the intestinal lumen In the liver; ’ play a role in the movement of cholesterol and plant sterols into the bile Lipoprotein Receptors Niemann-Pick C1-Like 1 (NPC1L1) ’ expressed in the intestine ’ mediates the uptake of cholesterol and plant sterols from the intestinal lumen into the enterocyte. Lipoprotein Lipase  a hydrolase  not normally found in blood  bound to heparan sulfate proteoglycans on the surface of the vascular endothelial cells  in heart, adipose tissue, spleen, lung, renal medulla, aorta, diaphragm, and lactating mammary gland  not active in adult LIVER. Lipoprotein Lipase ’ Cofactors ’ Phospholipids ’ apoCII ’ Inhibitors ’ apoAII ’ apoCIII ’ Triacylglycerols is hydrolyzed to : FFAs + glycerol. ’ Most of the released FFAs are transported into the tissue Lipoprotein Lipase ’ HEART lipoprotein lipase has a lower Km than ADIPOSE TISSUE lipoprotein lipase ’ [In the starved state; FFAs are redirected from ADIPOSE TISSUE to the HEART] In cause if stravation most FFA are directed from tissues to heart why ? Which one the statments below is correct about lipoprotein lipase? Lipoprotein lipase id inhibyaed by Apo a 2 and apoc 3 Adipose tissue has lower Km value. Hepatic Triglyceride Lipase (HTGL) ’ is bound to the sinusoidal surface of liver cells (limited to LIVER) Hepatic triglycerides lipase is activated by apoc3 just like lipoprotein lipase. ’ a hydrolase Fasle (hydrolyze triacylglycerol and phospholipid in lipoprotein) HTGL can be found in adipose tissue just like apo E recepters (remove triacylglycerols from lipoproteins) ’ no requirement for apoCII Hepatic Triglyceride Lipase (HTGL) ’ does not react with chylomicrons or VLDL (acts on particles partially digested by lipoprotein lipase ) Which one of the statements below is wrong about tha ’ react with chylomicron remnant and HDL metabolism enzyme that converts IDL to LDL ? It dose not require apoc2 for activation ’ may convert VLDL remnants to LDL It reacts with chylomicrons and HDL Facilities HDL uptake (conversion of IDL into LDL ) ’ may facilitate HDL uptake into LIVER. Hepatic Triglyceride Lipase (HTGL) ’ attaches to hepatocyte heparin sulfate (like lipoprotein lipase) ’ is released by heparin. ’ has postheparin lipolitic activity Lecithin Cholesterol Acyltransferase (LCAT) Apo A1 up regulation means LCAT up regulation ’ a glycoprotein enzyme ’ synthesized in the LIVER ’ activated by apoAI (on the surface of nascent HDL particles) Lecithin Cholesterol Acyltransferase (LCAT) ’ Catalyzes transfer of a FFA from lecithin to free cholesterol. LECITHIN + CHOLESTEROL ➜➔ LYSOLECITHIN + CHOLESTERYL ESTER ’ responsible for synthesis of most of the cholesterol esters in plasma Acyl-CoA Cholesterol Which one of the enzymes below sterify Acyltransferase (ACAT) cholesterol within cells ? ’ Esterifies cholesterol within cells (Different than LCAT) ’ ACAT1 : in macrophages ’ ACAT2 : in the intestine and liver. Phospholipid Transfer Protein (PLTP) ’ Transfers phospholipids (lecithin) (from VLDL, IDL, LDL to HDL) Cholesterol Ester Transfer Protein (CETP) ’ synthesized and secreted from liver. ’ transfers cholesterol esters from HDL to VLDL, IDL and LDL (in exchange for TG)  CELLS CAN OBTAIN FATTY ACIDS FROM  EXOGENEOUS PATHWAY The body gets fats from the outside.  ENDOGENEOUS PATHWAY The body makes its own fats.  CELLS CAN OBTAIN FATTY ACIDS FROM 1. fats in the diet 2. fats stored in adipose tissue 3. fats synthesized from excess dietary carbohydrates in the liver Chylomicron  84 % Triglycerides  8 % Cholesterol and Cholesterol esters  7 % Fosfolipid (Triglycerides and cholesterol esters are concentrated in the core) Chylomicron Metabolism In SMALL INTESTINE ’ Triacylglycerols in food are solubilized by bile salts ’ Pancreatic Lipase converts triacylglycerols to Monoacylglycerols Diacylglycerols Free fatty acids Glycerol (diffused into the intestinal mucosa) Chylomicron Metabolism In the ENTEROCYTE Nascent chylomicrons are assembled : ’ in the golgi / ER ’ FFAs are resterified ’ apoB48 apoAI, apoAIV are added. Chylomicron Metabolism Chylomicrons are released from the enterocyte into the lymphatic system enter the plasma via the left thoracic lymph duct. Chylomicron Metabolism In PLASMA ’ Chylomicrons picks up apoC and apoE from HDL ’ Chylomicrons reach peripheral tissues Chylomicron Metabolism ’ apoCII activates lipoprotein lipase ’ in the capillaries of adipose, heart, skeletal muscle, and lactating mammary tissues ’ hydrolyzes triacylglycerols to FFAs and glycerol ’ FFAs are released to these tissues. Chylomicron Metabolism In MUSCLE ’ FFAs are oxidized for energy Chylomicron Metabolism In ADIPOSE TISSUE ’ FFAs are reesterified for storage as triacylglycerols Adipose tissue has lipoprotein lipase  CII is tracked by lipoprotein lipase  Lipoprotein lipase break down triacylglycerols  FFAs is formed in adipose tissue Chylomicron Metabolism Chylomicron Metabolism Increase in insulin means protein kinase B(AKT ) up regultion inhabation of protein kinase A and Increased insulin stimulates lipoprotein lipase activation of lipoprotein lipase ’ Lipoprotein Lipase on surface of HEART has a higher affinity (lower Km) for lipoprotein substrates. ’ The Km for MUSCLE lipoprotein lipase is lower than that of lipoprotein lipase in ADIPOSE TISSUE. Chylomicron Metabolism FED STATE Why do we not ’ Chylomicron synthesis is high. see a a sifft in lipoprotein ’ Lipoprotein lipase activity is high. lipase activity of heart in ’ Storage of FFA as TG in adipose is high. fasted sate ? FASTED STATE ’ Chylomicron synthesis is low. ’ Lipoprotein lipase activity in adipose is low ’ Lipoprotein lipase activity in heart and other muscles remains steady Chylomicron Metabolism When triacylglycerols is removed from chylomicron ’ the size of the chylomicron is reduced ’ the loss of apoCII (returns to HDL) (no longer lipoprotein lipase activity) ’ apoB48 and E is retained = Chylomicron remnant Chylomicron Metabolism Chylomicron remnants: ’ depleted of most of their triacylglycerols ’ Acquire some cholesterol esters from the HDL ’ enriched in cholesterol and cholesteryl esters Chylomicron Metabolism ’ Chylomicron remnant has half diameter of the nascent chylomicron ’ The change in particle size uncovers apoE ’ apoE mediates the remnant binding to the apoB/E receptor and to the LRP in the LIVER. Chylomicron Metabolism ’ Chylomicron remnants travel to the LIVER. ’ apoE in the chylomicron remnants bind to LDL receptors in the liver. ’ LRP (= LDL receptor-related protein) are believed to take part. ’ Liver take up chylomicron remnants by endocytosis. Chylomicron Metabolism In the LIVER ’ Chylomicron remnants release their cholesterol ’ Chylomicron remnants are degraded in lysosomes. [The half-life of chylomicrons in plasma is less than 1 hour] Chylomicron Metabolism In the LIVER cholesterol is used to make ’ Glucose ’ Apolipoproteins ’ Bile acids ’ Hormones Chylomicron Metabolism VLDL  50 % Triglycerides  22 % Cholesterol and Cholesterol esters  18 % Fosfolipid ’ apoB100 (structural, binds to LDL receptor) ’ apoCII (activates lipase) ’ apoE (binds to LDL receptor) VLDL TRIACYLGLYCEROLS OF VLDL COMES FROM ’ FFAs of adipose tissue ’ Excess carbohydrate ’ Lipoproteins VLDL METABOLISM In the LIVER: ’ Excess carbohydrate and FFAs in the diet are converted to triacylglycerols ’ Triacylglycerols are packaged into VLDLs ’ apoB100 is essential for VLDL formation VLDL METABOLISM In PLASMA ’ Take the apoproteins (apoC, apoE) from HDL ’ Take cholesterol esters from HDL ’ Give triacylglycerols to HDL VLDL to mature is called cholesterol transfer protein VLDL METABOLISM VLDL METABOLISM The VLDLs are transported to  ADIPOSE TISSUE  MUSCLE Binding to VLDL receptor Activation of lipoprotein lipase by apoCII Releasing of FFAs from the triacylglycerols in VLDL VLDL METABOLISM In ADIPOSE TISSUE ’ FFAs are reconverted to triacylglycerols, and store. In MUSCLE ’ FFAs are oxidized to supply energy. VLDL METABOLISM REMNANT VLDL = INTERMEDIATE DENSITY LIPOPROTEIN (IDL) Apo c is seenin IDL.  31 % Triglycerides False  29 % Cholesterol and Cholesterol esters  22 % Fosfolipid Why is IDL doesn’t have apoc2 ’ apoCII (returns to HDL) ’ apoB100 ’ apoE VLDL METABOLISM apoE of VLDL ’ can not bind to apoB/E receptor apoE of Remnant VLDL (IDL) ’ can bind to apoB/E receptor VLDL METABOLISM 60-70 % of IDL 1. can be taken up by the LIVER directly via the LDL (apoB100, E) receptor with apoE 30-40 % of IDL 2. is converted to LDL ’ Each LDL particle is derived from only one VLDL particle LDL IDL does nit have Apoc2 , LDL dose not have apoe  Removal of triacylglycerols from VLDL and IDL produces LDL LDL contain :  8 % Triglycerides  50 % Cholesterol and Cholesterol esters  21 % Fosfolipid apoB-100 apo E  The main carrier of cholesterol in plasma  LDLs carry cholesterol to extrahepatic tissues. LDL METABOLISM ’ Most cells synthesize their own cholesterol ’ When the concentration of intracellular cholesterol decreases, cells take cholesterol from the outside This is mediated by : Sterol Regulatory Element-Binding Proteins (SREBPs) LDL METABOLISM Sterol Regulatory Element-Binding Proteins (SREBPs) ’ Transcription factor Which one of the gens below are regulated by SREBP. ’ Regulate the genes : ’ 3-Hydroxy-3-methylglutaryl coenzyme Synthase ’ HMG-CoA reductase ’ apoB/E LDL METABOLISM Sterol Regulatory Element-Binding Proteins (SREBPs) ’ Cholesterol levels are decreased ’ SREBP is transported from the endoplasmic reticulum to the golgi ’ In golgi; SREBP is cleaved by proteases and activated ’ SREBP migrates to the nucleus ’ Expression of LDL receptors is stimulated PCSK9 regulates the rate of degradation of LDL receptors. PCSK9 inhibitors are a new class of drugs that lower LDL. LDL METABOLISM  LDL are taken up through the apoB/E receptor 70 % of LDL 1. are taken by the LIVER 30 % of LDL 2. are taken by the peripheral cells LDL METABOLISM ’ LDL receptors on the extrahepatic tissues recognize apo B-100. ’ LDL bind to an LDL receptor. ’ Endocytosis is initiated. ’ LDL and its receptor move into the cell within an endosome. ’ The endosome eventually fuses with a lysosome. LDL METABOLISM ’ The lysosome hydrolyze the cholesteryl esters ’ Cholesterol and FFAs are released into the cytosol ’ apoB-100 of LDL is degraded to amino acids that are released to the cytosol. ’ LDL receptor is returned to the cell surface to function again LDL METABOLISM ’ apoB-100 is also present in VLDL ’ The receptor-binding domain of VLDL is not available for binding to the LDL receptor. ’ Conversion of VLDL to LDL exposes the receptor-binding domain of apoB100. LDL METABOLISM LDL receptor (apoB/E receptor) ’ specific for apoB100 (not apoB48) ’ also bind to apoE Chylomicrons and VLDL remnants contain apoE apoE plays a role in the hepatic uptake of them (This receptor is defective in familial hypercholesterolemia) LDL receptor (apoB/E receptor) If LDL receptors are unavailable ’ VLDL remnants and chylomicrons bind to lipoprotein receptor-related protein (LRP) via apoE. HDL HDL contain:  4 % Triglycerides  30 % Cholesterol and Cholesterol esters  29 % Fosfolipid HDL APOPROTEINS ’ apoAI, apoAII ’ apoCI, apoCII ’ apoD, apoE ApoAI is the major HDL is an plasma reservoir of Apoc and ApoE (apoC and apoE are required in the metabolism of chylomicrons and VLDL) HDL ’ HDL-2 : larger, less dense particles ’ HDL-3 : smaller, more dense particles HDL METABOLISM Nascent HDL Only HDL contains APO C And APoB in nasecent state ’ disk-shaped ’ lipid poor particles (pre-β HDL) ’ contain mainly apoAI (activator of LCAT) (also contain apoC and/or apoE) ’ contain free cholesterol. Mature HDL ’ spherical-shaped HDL METABOLISM -1 Nascent HDL ’ go to the periphery (vessel) and pick up cholesterol Mature HDL ’ give cholesterol to LDL ’ 80% of this LDL goes to the liver ’ 20 % of this LDL goes back to the periphery HDL METABOLISM -2 Nascent HDL ’ goes to the periphery and pick up cholesterol Mature HDL ’ go to the peripheral tissue ’ Liver ’ Testis ’ Ovary ’ Adrenal medulla  the hormones are produced HDL METABOLISM -3 Nascent HDL ’ go to the periphery (vessel) and pick up cholesterol Mature HDL ’ goes to the peripheral tissues and pick up more cholesterol (SRB1 receptor, ABCA1 receptor) ’ HDL Metabolism -1 ’ HDL Metabolism -2 HDL METABOLISM Synthesis of HDL begins with the secretion of apoAI from the LIVER and INTESTINE apoA1 ’ synthesized and secreted from BOTH in liver and intestine ’ chief protein of HDL ’ secreted in a lipid-poor form HDL HDL METABOLISM apoC and apoE ’ are synthesized in the LIVER ’ are transferred from liver HDL to intestinal HDL when the latter enters the plasma. HDL METABOLISM Nascent HDL (= preB-HDL) ’ consists of discoid phospholipid bilayer containing apoA and free cholesterol. HDL METABOLISM How does HDL get cholesterol? apoA1 ’ collect additional phosphatidylcholine, cholesterol, and cholesteryl esters via the ABCA1 pathway ABCA1 transporter/receptor ’ ATP-binding cassette transporter A1 ’ Preferentially transfer cholesterol from cells to poorly lapidated particles (preHDL or apoA1) HDL METABOLISM TANGIER DISEASE ’ a mutation in the gene coding for the ABCA1 transporter. ’ almost no HDL ’ deposition of cholesteryl esters in tissues  The patients suffer from coronary disease more frequently than others HDL METABOLISM ’ Nascent HDL acquires more lipid from other peripheral tissues and from lipoproteins (through the ABCA1 transporter) HDL METABOLISM Cholesterol bind to pre BHDL via ABCA1 pathway but closterols get stratified by LCAT apoA1 activates LCAT  Lecithin Cholesterol Acyltransferase (LCAT) binds to preβ-HDL  Cholesterol is esterified with FFAs from lecithin.  Cholesteryl esters are formed. ’ Cholesteryl esters move into the interior of the HDL ’ = HDL-3 (spherical shape) HDL METABOLISM Lecithin Cholesterol Acyltransferase (LCAT) ’ Second carbon of lecithin contains PUFA ’ PUFA is transferred to 3rd OH group of cholesterol to form cholesterol esters. HDL METABOLISM Cholesterol Ester Transfer Protein (CETP) ’ HDL-3 give some cholesteryl esters to triglyceride-rich lipoproteins (Cholesterol esters reenter the VLDL-IDL-LDL pathway) ’ HDL-3 take some triglycerides ’ = HDL-2 HDL METABOLISM ’ Mature HDL (= a-HDL) is formed ’ α-HDL particles have a much longer half-life than the smaller preβ- HDL. HDL METABOLISM HDL off load some of their cholesteryl esters ’ in the LIVER ’ in STEROIDOGENIC ORGANS HDL METABOLISM ’ HDL-2 binds to the class B scavenger receptors in the LIVER ’ Hepatic lipase hydrolyzes HDL phospholipids and TAG ’ Cholesteryl esters is transferred to the cell membrane. ’ SCARB1, SRB1, SRBI equilibrate cholesteryl esters in HDL with cellular cholesteryl esters. HDL METABOLISM IN THE LIVER Cholesterol esters are used for the synthesis of bile acids or excreted as bile. HDL METABOLISM ’ HDL is not taken up by cells ’ = nascent HDL Nascent HDL: re-enter the cholesterol removal cycle. HDL METABOLISM  Hepatic lipase removes triacylglycerols from the HDL.  Poorly lipidated HDL is formed HDL METABOLISM FUNCTIONS OF HDL ’ Scavenges extra cholesterol from peripheral tissues ’ Competes with LDL for binding sites on the membranes and prevents internalization of LDL in the smooth cells of arterial walls. ’ Contributes its apoC and apoE to nascent VLDL and chylomicrons ’ Stimulated prostacylin synthesis by the endothelial cells, which prevent thrombus formation ’ Helps in the removal of macrophases from the arterial walls. HDL METABOLISM Anti-atherogenic effects of HDL PATHWAYS OF LIPOPROTEIN METABOLISM FUEL TRANSPORT PATHWAY VLDL and CHYLOMICRONS METABOLISM ’ transport of triacylglycerols ’ closely linked to the REVERSE CHOLESTEROL TRANSPORT OVERFLOW PATHWAY LDL METABOLISM ’ from the stage of hydrolysis of remnant particles by hepatic triglyceride lipase to LDL uptake by cells REVERSE CHOLESTEROL TRANSPORT HDL METABOLISM PATHWAYS OF LIPOPROTEIN METABOLISM Lipoprotein (a)  consists of an LDL molecule and Apo (a) , (Apo (a) is attached to the Apo B-100 of the LDL via a single disulfide bound)  Molecular weight of apo (a) can range from 250,000 to 800,000.  Individuals with high molecular weight Apo (a) proteins tend to have lower levels of Lp (a).  Elevated plasma Lp(a) levels are associated with an increased risk of atherosclerosis.  Therapies that accelerate LDL clearance and lower LDL levels do not lower Lp (a) levels.  The kidney appears to play an important role in Lp (a) clearance HYPOLIPOPROTEINEMIAS ABETALIPOPRTEINEMIA ’ A rare disease ’ Lipoproteins containing apoB are not formed ’ (No chylomicrons, VLDL, or LDL) ’ Defect in the loading of apoB with lipid ’ Lipid droplets accumulate in the INTESTINE and LIVER HYPOLIPOPROTEINEMIAS FAMILIAL ALPHA-LIPOPROTEIN DEFICIENCY ’ Absence of apoCII ’ Low or near absence of HDL ’ Hypertriacylglycerolemia ’ Low LDL levels HYPOLIPOPROTEINEMIAS TANGIER DISEASE FISH EYE DISEASE apoAI DEFICIENCIES HYPERLIPOPROTEINEMIAS HYPERLIPOPROTEINEMIA type I ’ Decreased or abnormal lipoprotein lipase ’ or apoCII deficiency ’ Slow clearance of chylomicrons and VLDL ’ Chylomicrons are increased ’ Low levels of LDL and HDL ’ Hypertriacylglycerolemia ’ No increased risk of coronary disease HYPERLIPOPROTEINEMIAS HYPERLIPOPROTEINEMIA type IIA ’ FAMILIAL HYPERCHOLESTEROLEMIA ’ LDL receptor deficiency ’ LDLs are increased ’ Hypercholesterolemia ’ Atherosclerosis and coronary disease HYPERLIPOPROTEINEMIAS HYPERLIPOPROTEINEMIA type III ’ FAMILIAL DYSBETALIPOPROTEINEMIA ’ Defect in apoE2 synthesis ’ Chylomicron remnants and VLDL remnants (IDLs) are increased ’ Causes hypercholesterolemia xanthomas and atherosclerosis HYPERLIPOPROTEINEMIAS HYPERLIPOPROTEINEMIA type IV ’ FAMILIAL HYPERTRIACYLGLYCEROLEMIA ’ Increased VLDL production and decreased elimination ’ VLDLs are increased ’ subnormal LDL and HDL ’ High cholesterol ’ often associated with glucose intolerance and hyperinsulinemia, alcoholism, diabetes mellitus and obesity OBESITY ’ increased synthesis of VLDL ’ increased flux through the fuel transport pathway WEIGHT LOSS ’ decreases the activity of fuel transport pathway ALCOHOL ABUSE ’ increased synthesis of VLDL ’ Increase HDL concentration DIABETIC DYSLIPIDEMIA ’ lack of insulin ’ The fuel transport pathway is overloaded ’ the reverse cholesterol transport is affected ’ suppression of lipoprotein lipase ’ hydrolysis of chylomicrons or VLDL is inefficient. ’ an increase in plasma triacylglycerol concentration ’ a decrease in HDL ’ normal LDL (the overflow pathway is unaffected) ’ diabetic LDL are more atherogenic (LDLs are smaller and denser) than the nondiabetic particles Lipoprotein(a) ’ Lp(a) ’ a low-density lipoprotein ’ consists of an LDL like particle an apolipoprotein(a) ’ is assembled at the hepatocyte cell membrane surface ’ Interferes with plasminogen activation and impairs fibrinolysis. ’ contributes to the process of atherogenesis ’ predictor of coronary heart disease.