Lipoprotein Structures, Function and Metabolism (1)
Lecture Outline • What are lipoproteins? • What do they do? • Basic structure of lipoproteins • Lipoprotein metabolism • Hyperlipoproteinemia • Cholesterol and bile acid metabolism • Role of lipoproteins in atherosclerosis
What are lipoproteins? • Molecular complexes that consist of lipids and proteins. They function as transport vehicles for lipids in blood plasma. • Lipoproteins deliver the lipid components (cholesterol and triglyceride etc.) to various tissues for utilization.
Hydrophobic lipids Amphiphilic lipids
Structure of lipoprotein Hydrophobic lipids (TG, CE) in the core Amphiphilic lipids (C, PL) and proteins on the surface
Classification of plasma lipoproteins • according to their density • Chylomicron (CM) • Very low density lipoprotein (VLDL) • Intermediate density lipoprotein (IDL) • Low density lipoprotein (LDL) • High density lipoprotein (HDL)
Lipoproteins • Each contains different kinds and amounts of lipids and proteins • The more protein, the higher the density • The more lipid, the lower the density • Each has different function
Characteristics of human plasma lipoproteins CM VLDL LDL HDL Density (g/mL) <0.96 0.96-1.006 1.006-1.063 1.063-1.21 Diameter (nm) 100-1000 30-90 20-25 10-20 Apolipoprotein A,C,E,B48 A,C,E,B100 B100 A,C,D,E Composition (%) Proteins 2 10 20 40 Lipids 98 90 80 60 Lipid composition (%) TG 88 55 12 12 CE+C 4 24 59 40 PL 8 20 28 47 Free fatty acid - 1 1 1
Classification of plasma lipoproteins according to their electrophoretic mobility (CM) 1967, Fredrickson et al. a-lipoprotein (HDL) Pre-b-lipoprotein (VLDL) b-lipoprotein (LDL) CM
LPL (Lipoprotein Lipase) • Locate in extracellular on the walls of • blood capillaries, anchored to the endothelium. • Hydrolyze triglyceride (TG) in the core of • CM and VLDL to free fatty acids and glycerol. • The free fatty acids are transported into the • tissue, mainly adipose, heart, and muscle (80%), • while about 20% goes indirectly to the liver.
HL(Hepatic Lipase) • Bound to the surface of liver cells, • Hydrolyzes TG to free fatty acids and glycerol • Unlike LPL, HL does not react readily with • CM or VLDL but is concerned with TG • hydrolysis in VLDL remnants and HDL metabolism
LCAT • (Lecithin:Cholesterol Acyltransferase) • Formation of cholesterol esters in lipoproteins
CETP (Cholesterol Ester Transfer Protein)
Apolipoproteins • Act as structural components of lipoproteins • Recognize the lipoprotein receptors on cell membrane surface as ligand • Activate/inhibit enzymes involved in lipoprotein metabolism
Apo AI: Activator LCAT • Apo AII: Inhibitor of hepatic lipase (HL) • Apo A-IV: Activator of LCAT • Apo B-100 (liver, 4564 Aa): structure, ligand • Apo B-48 (intestine, 2152Aa): structure • Apo C-I : Activator of LCAT • Apo C-II: Activator of LPL • Apo C-III: Inhibitor of LPL • Apo D: Function unknown • Apo E: Ligand
In liver In intestine ApoB100 and ApoB48 come from same gene
What do lipoproteins do? • Serve to transport lipids and lipid-soluble compounds between tissues and organs • Substrates for energy metabolism (TG) • Essential components for cells (PL, C) • Precursors for hormones (C) • Lipid soluble vitamins • Precursors for bile acids (C)
Metabolism of chylomicrons Surface Monolayer Phospholipids Free Cholesterol Protein Hydrophobic CoreTriglyceride Cholesteryl Esters
Metabolism of chylomicrons • Transport dietary TG and Cholesterol from the intestine to the peripheral tissues • The dietary TG are first acted by intestine lipase and absorbed as monoacylglycerol, fatty acid and glycerol. Within the intestine cells, they are resynthesized into TG. • CM are synthesized in the intestine using TG, PL, C, ApoB48, and ApoAs and secreted into the lymph and reach blood through thoracic duct. • Nascent CM pick up apoE, apoCs and some apoAs from HDL.
In the capillaries of peripheral tissue, lipoprotein lipase (LPL) degrades triglycerol (TG) of chylomicrons to fatty acids (FA) and glycerol which enter tissues by diffusion Lipoprotein lipase (LPL) is activated by apo C-II After most of the TG is removed, chylomicrons become chylomicron remnants. During the process, CM give apoC and apoA to HDL Metabolism of chylomicrons
Metabolism of chylomicrons • CM remnants bind to specific receptors on the surface of liver cells through apo E and then the complex is endocytosed. • remnant receptor or • apoE receptor or • LRP (LDL receptor-related protein) • Chylomicron remnants deliver dietary cholesterol and some cellular cholesterol (via HDL) to the liver. • Half life of CM is short, less than 1 hour.
Metabolic fate of chylomicrons. (A, apolipoprotein A; B-48, apolipoprotein B-48; , apolipoprotein C; E, apolipoprotein E; HDL, high-density lipoprotein; TG, triacylglycerol; C, cholesterol and cholesteryl ester; P, phospholipid; HL, hepatic lipase; LRP, LDL receptor-related protein.) Only the predominant lipids are shown.
VLDL • VLDL are made by liver. Liver synthesizes TG and cholesterol and packages them into VLDL for export into blood. • Most lipid in the core of VLDL is triglyceride • Nascent VLDL contain apoB100. In blood nascent VLDL pick up apoE and apoCs from HDL and become matured VLDL.
VLDL • In the capillaries of various tissues, LPL degrades TG to fatty acids and glycerol, which enter the tissues by diffusion. ApoC-II is needed in this step to activate LPL. • When VLDL loses triglyceride, it transforms into VLDL remnant, also named as IDL (intermediate-density lipoprotein). • During the process, some apolipoproteins (apo As and apoCs) are transferred back to HDL. • VLDL function: Deliver TG from liver to peripheral tissue cells.
VLDL remnant Fates of VLDL remnants (IDL) • Results from loss of TG in VLDL • Contains relatively more cholesterol esters • Taken up by liver or transform into LDL • 1) A proportion of the VLDL remnant (IDL) is taken up by liver through the LDL receptor (apoE-mediated). • 2) The other remnant is further acted upon by hepatic lipase (HL) and converted into LDL. LDL loses all apolipoproteins except apoB100.
LDL Most core lipid in LDL is cholesterol ester. ApoB100 is only apolipoprotein in the surface.
LDL receptor • Also named as apoB-100/apoE receptors • LDL receptors exist in the liver and in most peripheral tissues • The complexes of LDL and receptor are taken into the cells by endocytosis, where LDL is degraded but the receptors are recycled • LDL cholesterol levels are positively related to risk of cardiovascular disease • Therefore, cholesterol in LDL has been called “bad cholesterol”