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. Inner droplet of neutral (water-insoluble core lipids); primarily triglycerides and cholesteryl esters A solubilizing surface layer of phospholipids and unesterified cholesterol Specific proteins (apolipoproteins) attached to the outer lipid layer through their specific lipophilic domains

Hydrophobic lipids Amphiphilic lipids

In phospholipids X=

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

Important enzymes and proteins involved in lipoprotein metabolism

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

(Lecithin:Cholesterol Acyltransferase) 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 Core Triglyceride 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.

Metabolism of chylomicrons 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 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 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.

Metabolism of VLDL and LDL

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.

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. Major cholesterol carrying lipoprotein 2/3 - 3/4 of serum cholesterol is carried by LDL 50% of mass is cholesterol Produced as a product of VLDL metabolism Delivers cholesterol to peripheral tissues for biosynthesis and steroid hormone production 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”