Lipid Metabolism Part II: Lipoproteins PDF

Lipid metabolism Part II: metabolism of lipoproteins Zhang, Dong PhD, Professor Biomedical Sciences Department [email protected] Harvey and Ferrier: Lippincott Biochemistry 8th Edition: Chapter 15 and 18 Marks’ Basic Medical Biochemistry, 6e, Chapter 32 and 34 Office of Academic Affairs ...

Lipid metabolism Part II: metabolism of lipoproteins Zhang, Dong PhD, Professor Biomedical Sciences Department [email protected] Harvey and Ferrier: Lippincott Biochemistry 8th Edition: Chapter 15 and 18 Marks’ Basic Medical Biochemistry, 6e, Chapter 32 and 34 Office of Academic Affairs  Learning Objectives 1. Explain the digestion and absorption of dietary lipids 2. Illustrate the function of the chylomicron pathway 3. Explain the causes and consequences of fat malabsorption 4. Compare and contrast the life cycle of the various lipoprotein particles (VLDL, IDL, LDL, and HDL) with respect to their functions, composition, metabolism and transport.  The structure of plasma lipoproteins - I Both triglyceride (or triacylglycerol) and cholesterol may be absorbed from diet or synthesized in the body (de novo). They cannot be transported as free molecules due to their nonpolar nature Triglyceride and cholesterol are transported in plasma as lipoproteins – complexes of lipids and proteins (apoproteins). Lipoproteins are mixed micelles consisting of a core of nonpolar triglycerides and cholesterol (esters) surrounded by a surface layer of phospholipids and apoproteins.  The structure of plasma lipoproteins - II Triglycerides are low density. Proteins are high density. So, the more triglycerides in a lipoprotein, the lower its density. Lipoproteins can be separated from each other by electrophoresis or density gradient centrifugation.  The functions of lipoproteins Functions: “Solubilize” insoluble lipids for transport Transport both dietary and endogenous lipids Classification: Chylomicrons transport dietary lipids from intestine to liver and tissues VLDLs transport endogenous lipids from liver to tissues LDLs deliver cholesterol from liver to tissues with large cholesterol needs (adrenals, sex glands, etc.) HDLs transport cholesterol from tissues back to liver  Major classes of lipoproteins The more triglyceride in a lipoprotein, the lower its density: Chylomicrons (the least dense) Very low density lipoproteins (VLDL) Intermediate density lipoproteins (IDL) Low density lipoproteins (LDL) High density lipoproteins (HDL) (the most dense) (nm)  Structural features of plasma lipoproteins -apoproteins Chylomicron VLDL IDL LDL HDL Shell: phospholipids and other amphipathic molecules on the surface Core contains lipids (triglyceride and cholesterol esters) Apoproteins (also amphipathic) are also on the surface – some functional, some structural – can activate enzymes (e.g., apoAI, apoCII) or act as ligands for receptors (e.g. apoE) The three major pathways of lipoprotein metabolism The chylomicrons/chylomicron remnants pathway: distributes dietary triglycerides and cholesterol to liver and peripheral tissues The very low density lipoproteins (VLDL)/intermediate density lipoproteins (IDL)/low density lipoproteins (LDL) pathway: transports triglycerides and cholesterol out of liver to the peripheral tissues The nascent/mature high density lipoprotein (HDL) pathway: transports cholesterol from peripheral tissues back to liver Transport of dietary lipids - Chylomicrons Plasma lipoproteins and the transport of dietary lipids - overview Dietary (exogenous) TG: triglyceride 2-MG: 2-monoacylglycerol FA: fatty acid LPL: lipoprotein lipase Transport of dietary lipids by chylomicrons - synthesis Chylomicrons: synthesized in the intestinal epithelial cells with dietary lipids ApoB-48 is synthesized in ER, lipids are then loaded on, secreted from Golgi. Lipids loaded onto ApoB-48 by MTP (Microsomal triglyceride Transfer Protein). Defect in MTP causes Abetalipoproteinemia Secreted into the lymphatic system Enter the blood through the thoracic duct Transport of dietary lipids by chylomicrons – ApoB-48 ApoB-48 is produced by RNA editing of the ApoB-100 gene  RNA editing takes place in the intestine  C edited to U creates a STOP codon VLDL, IDL, LDL Chylomicron  Transport of dietary lipids by chylomicrons – maturation and fate Maturation - transfer of apoproteins from HDLs to nascent chylomiscrons:  ApoCII and ApoE are transferred to nascent chylomicrons to form mature chylomicrons o ApoCII stimulates LPL o ApoE recognized by receptors Fate - Lipoprotein lipase (LPL) hydrolyzes the TGs of the chylomicron: LPL is attached to proteoglycans on the basement membrane of capillary endothelium LPL is high in adipose tissues, muscle, and mammary gland o Insulin stimulates LPL synthesis in adipose tissues LPL is activated by ApoCII o Released fatty acids may enter the cell or bind albumin in blood o glycerol used by the liver for lipid synthesis, glycolysis, or gluconeogenesis The remaining chylomicron is called chylomicron remnant, taken up by liver  The activity of LPL Fatty acids are removed from triglycerides one at a time by LPL, which adds a water molecule across the ester bond.  Transport of dietary lipids by Chylomicrons - fate Chylomicron remnants decrease in size and increase in density ApoCII returns to HDLs Chylomicron remnant taken up by the liver hepatocytes o Bound to the hepatocyte apoE Receptor via apoE o Taken into hepatocytes as endosomes o Endosomes fuse with lysosomes o Contents in endosomes hydrolyzed and used by liver cells Clinical issues Fat malabsorption: Possible causes – Pancreatic failure (pancreas secrets a variety of digestive enzymes including lipase and colipase**) – Lack of bile salts (bile duct blockage) – Intestinal diseases Malabsorption causes Steatorrhea with bulky fatty stools Decrease in fat soluble vitamin absorption (D,E,A,K) because they are absorbed via the Chylomicron pathway **Colipase: 1) Anchors lipase at the lipid-aqueous interface 2) Restores activity to lipase in the presence of inhibitory substances like bile salts that bind the micelles. Transport of endogenous lipids – VLDL, IDL, LDL and HDL  Transport of endogenous lipids by VLDL-I VLDLs are synthesized in liver from endogenous lipids (mainly from excess carbohydrates) – Secreted into the hepatic veins as nascent VLDL – Accept apoE and apoCII from HDL in the blood and become mature VLDL – Function to carry the lipids to peripheral tissues: muscle (used as energy), adipose (storage) etc. ApoB-100 is the structural apoprotein of VLDL Microsomal triacylglycerol transfer proteins (MTP) load lipids with ApoB-100 to form VLDL Lipoprotein lipase (LPL) digests the TGs of the VLDL Transport of endogenous lipids by VLDL: ApoB-100 VLDL Chylomicron IDL LDL  Transport of endogenous lipids by VLDL-II VLDL becomes VLDL remnant or IDL after losing TG – IDL taken up by liver hepatocytes via apoE receptor – IDL can also be further metabolized to become LDL particles successive action of LPL/HTGL to hydrolyze TG remaining LDL is rich in cholesterol (from HDL) – LDL taken up by liver or peripheral tissues binds to LDL receptor via apoB-100 HTGL: hepatic triglyceride lipase LDLs provide cholesterol to peripheral tissues high LDL levels can saturate uptake by liver – Excess and oxidized LDL taken up by macrophages – (forms foam cells then plaque - atherosclerosis)  The LDL receptor The LDL receptor is found in many tissues. The LDL receptor is an integral protein of six regions. The amino terminal domain is negatively charged and interacts with the apoB-100 protein of LDL. The receptor also binds to apoE (found in VLDL and Chylomicron remnants). Cellular uptake and degradation of LDL Following LDL binding, the receptor-LDL complex is internalized by endocytosis. These vesicles fuse with lysosomes where the proteins in the LDL are hydrolyzed. The cholesteryl esters are hydrolyzed to liberate free cholesterol inside the cell. The receptor returns to the membrane.  Transport of endogenous lipids by VLDL - III Inside the cell, free cholesterol can be re-esterified by Acyl CoA:Cholesterol AcylTransferase (ACAT) – Esterification keeps cholesterol out of the cytoplasmic membrane – Usually esterified to oleate (18:1) or palmitolate (16:1) – LDL cholesterol ester usually linoleate (18:2) LDL receptor synthesis down-regulated by cholesterol – Involves SREBP (as discussed in the cholesterol synthesis lecture) Niemann-Pick type C disease cannot release cholesterol from lysosome – Cholesterol builds up in lysosomes – Cells (nerve cells) die → early death HDL in reverse cholesterol transport  HDL in reverse cholesterol transport-I HDL is synthesized mainly in the liver and intestine – Nascent HDL particle is disk-shaped, containing primarily phospholipids – Contains/transfers several apoproteins (ApoA, ApoE, and ApoCII; others) – Mature HDL also called HDL3 (accumulating some cholesterol, next slide), globular- shaped – High cholesterol HDL also called HDL2 (atherogenic protective, next slide) HDL plays a major role in reverse cholesterol transport (vasculo-protective) – HDL picks up free cholesterol from the cell membranes of extrahepatic tissues and transfers them to liver or VLDL  HDL in reverse cholesterol transport-II Cells get rid of cholesterol by reverse cholesterol transport – ABC1 (an ATPase, also known as ABCA1) moves cholesterol from inner leaflet of plasma membrane to outer leaflet o Tangier disease: ABCA1 deficiency → reduced HDL – Cholesterol is then transferred to HDL HDL picks up cholesterol from extrahepatic cells – Requires 2 enzymes LCAT (aka PCAT-phosphatidylcholine) = Lecithin: cholesterol acyl transferase (activated by Apo A1) CETP = Cholesterol ester transfer protein HDL in reverse cholesterol transport-III HDL picks up cholesterol from extrahepatic cells requires 2 enzymes (LCAT and CETP): LCAT - lecithin cholesterol acyl transferase – Activated by Apo A1 – synthesizes cholesterol ester (CE) PL – FA comes from Phosphatidylcholine (lecithin) – traps cholesterol in the HDL CETP - cholesterol ester (CE) transfer proteins – transfers cholesterol ester to VLDL in exchange for triglyceride (TG) and phospholipid (PL) PL HDL in reverse cholesterol transport-IV HDLs bind the scavenger receptor (SR-B1) on hepatocytes: – Cholesterol (C) and cholesterol ester (CE) transferred into the liver cell – no endocytosis (unlike the LDL receptor) – HDL dissociates and re-enters circulation – SR-B1 can be up-regulated by cells requiring cholesterol Chylomicrons Summary of plasma lipoproteins Produced in intestinal epithelial cells from dietary fat Carries triacylglycerol in blood VLDL Produced in liver mainly from dietary carbohydrates Carries triacylglycerol in blood IDL Produced in blood (remnant of VLDL after triacylglycerol digestion) Endocytosed by liver or converted to LDL LDL Produced in blood (remnant of IDL after triacylglycerol digestion; the end product of VLDL) Contain high concentration of cholesterol and cholesterol ester Endocytosed by liver and peripheral tissues HDL Produced in liver and intestine Exchanges proteins and lipids with other lipoproteins (e.g., chylomicrons, VLDL) Functions in the return of cholesterol from peripheral tissues to liver  Lp(a) - one last clinically important lipoprotein Lipoprotein(a), or Lp(a), is nearly identical to LDL. A distinguishing feature of Lp(a) is the presence of apoprotein(a), or apo(a) that is covalently linked to a Cys residue on apoB-100 apo(a) is structurally similar to plasminogen (a precursor of plasmin that degrade fibrin, a major component of blood clots.) High levels associated with increased risk of coronary heart disease – Levels mostly genetically controlled – High dietary trans fats associated with increased level of Lp(a) The physiological function of Lp(a) remains unknown. One hypothesis is that elevated level of Lp(a) slows the breakdown of blood clots that trigger heart attack because it competes with plasminogen for binding of fibrin Niacin (vit. B3) reduces Lp(a), as well as LDL-cholesterol and TAG, and raises HDL  Summary Key concepts: chylomicrons, VLDL, IDL, LDL, HDL, Lp(a), apoproteins, MTP, Lipoprotein lipase (LPL), Reverse Cholesterol Transport Synthesis, maturation and fate of chylomicrons, VLDL, IDL, LDL, HDL Biological functions of chylomicrons, VLDL, IDL, LDL, HDL Clinical correlations: disease symptoms, biochemical basis, and treatment (Abetalipoproteinemia, fat malabsorption, Steatorrhea, Niemann-Pick type C disease, Tangier disease)  Lecture Feedback Form: https://comresearchdata.nyit.edu/redcap/surveys/?s=HRCY448 FWYXREL4R