BIOC 801 - Dr. TischlerLecture 32 March 29, 2005LIPIDS: LIPOPROTEINS/TRANSPORT

Pathways of Lipid Transport & Inherited HyperlipidemiasFamilial HyperTriGlyceridemia LPL deficiency etc. RAREFamilial Combined Hypertriglyceridemia Polygenic. VERY COMMON (ApoB)Remnant Removcal Disease ApoE deficiency. UNCOMMON Familial Hypoalphalipoproteinemia (Tangiers Disease) HDL low. RAREFamilial Hyper- cholesterolemia LDL receptor deficiency. COMMON. Heterozygotes ~1:500.XX = HMG-coA Reductase step blocked by StatinsFrom: Knopp R.H. Drug Treatment of Lipid Disorders. N Engl J Med 1999:341:498-510

General Features of LipoproteinsApolipoproteins: specific lipid-binding proteins that attach to the surface intracellular recognition for exocytosis of the nascent particle after synthesisactivation of lipid-processing enzymes in the bloodstream, binding to cell surface receptors for endocytosis and clearance.

Main lipid components: triacylglycerols, cholesterol esters, phospholipids. Major lipoproteins: chylomicronsvery low density lipoproteins (VLDL)low density lipoproteins (LDL) high density lipoproteins (HDL)

Subfraction: intermediate density lipoproteins (IDL)

Electrophoretic mobility (charge):HDLs = lipoproteinsLDLs = -lipoproteins VLDLs = pre- lipoproteins (intermediate between and mobility).

Figure 1. Model of low density lipoprotein. Other lipoproteins have a similar structure differing in the core content of lipid and the type of apoproteins on the surface of the molecule

0%20%40%60%80%100%Chylo-micronsVLDLLDLHDLLipoprotein TypeCompositionFigure 2. The major classes of lipoproteins and their relative content of triacylglycerol (T), cholesterol (C) and protein (P).

LIVERApoB48 aids with chylo-micron assemblyLymph system:Chylomicrons to capillaries via lymphINTESTINEnon-hepatic tissuesFigure 3. Exogenous pathway of lipid transport. Chylomicrons carry dietary fatty acids to tissues and the remnants take cholesterol to the liver

Chylomicron (or VLDL)Apo CIILIPOPROTEIN LIPASEPolysaccharideChainEndothelialSurface of cellTriacylglycerolin coreFree fatty acidsGlycerolTo LiverFree fatty acidsIn cellulo (muscle & adipose)CapillaryFigure 4. Lipoprotein lipase action on chylomicron triacylglycerol (an identical reaction occurs with VLDL)

LIVERApoB48non-hepatic tissuesFigure 3. Exogenous pathway of lipid transport. Chylomicrons carry dietary fatty acids to tissues and the remnants take cholesterol to the liver

LIVERHDL scavenge cholesterolFigure 5. The liver-directed endogenous pathway of lipoprotein metabolism. non-hepatic tissuesLPL hydrolyze TAGs; FFA uptake; LDL circulate to tissuesapo B100 on LDL bind to receptorLDL taken into the cell to deliver cholesterol CII and E release to HDLApo E binds liver receptor Cholesterol uptake; excreted as bile acids

Nascent Chylomicron Assembly in Gut Mediated by B48Nascent HDL Assembled in liver Loans apo E/ apo CII to nascent chylomicronsMature Chylomicron Apo E and CII added from HDLLipoprotein Lipase capillary walls hydrolyzes TAG deliver FFA into adipose/muscleMature HDL CE from peripheral cells via LCAT activated by apo A1 Apo CII returned by chylomicrons

Chylomicron Remnant from mature chylomicron apo CII returned to HDLChylomicrons: Exogenous PathwayHDL: Both PathwaysFig. 6 Chylomicron Processing and Interface with HDLMature Chylomicron Apo E and CII added from HDL CII activates LPL

Lipoprotein Lipase capillary walls hydrolyzes TAG deliver FFA into adipose/muscleLDL from mature VLDLNascent VLDL Assembly in Liver Mediated by B100VLDL/LDL: Endogenous PathwayHDL: Both PathwaysFig. 6 VLDL/LDL Processing and Interface with HDLMature VLDL Apo E and CII added from HDLapo CII & E from HDLMature HDLApo CII/E returned by VLDL

Mature VLDL Apo E and CII added from HDL CII activates LPL

E ReceptorMature HDLCE MetabolismChylomicron Remnant E ReceptorB100receptorLDLFig. 6 Clearance of Cholesterol by Liver from Chylomicron Remnants, HDL and LDL

PathogenesisOxidized LDL

1. Uptake by "scavenger receptors" on macrophages that invade artery walls; become foam cells2. Elicits CE deposition in artery walls3. Atherosclerosis/CAD can develop

Figure 6. Consequence of Oxidized LDL FormationOxidation of LDLLDL

free pool ofcholesterol

LDLCEendocytosislate endosome ACEHCE cholesterolB100 amino acidsNPC-1 mediated transferCholesterol metabolism to bile acids or steroidsGolgi

MembraneCholesterol ACAT (stimulated by cholesterol)CECECE stored in dropletsCERPLCATMature HDL:Cleared by liveroooclathrin-coated pitooovesicleRecycling of receptortransport vesicle- lysosome fuse forming late endosome

sorting endosome: ligand/receptor dissociationlysosomeFigure 7. Cellular cholesterol uptake, metabolism and release. ReverseCholesterolTransportRecycling of receptor and clathrin

Lipoprotein classes:

Lipo-proteinSourceApo Proteins in MatureProtein:Lipid/Major (minor) Lipid TransportedFunctionChylo-micronsgutB48, CII*, E*1:49triacylglycerol (CE)Dietary:FFA Adipose/muscleCE Liver via remnantsVLDLliverB100, CII*, E*1:9triacylglycerol (CE)Synthesized:FFA adipose/muscleCE LDLLDLbloodB1001:3cholesterol esterCE to liver (70%) and peripheral cells (30%)HDLliverA1, CII, E("ACE")1:1cholesterol estersupplies apo CII, E to chylomicrons and VLDL; mediates reverse cholesterol transport

Functions of Apolipoproteins & Enzymes in Lipid Transport/Processing

Protein (Enzyme)Site of ActionActivatorFunctionLPL (Enzyme)capillary wallsapo CIIexcises FFA from TAGs in chylomicrons and VLDLs for adipose and muscleACAT (Enzyme)inside cellsfree cholescholesterol ester storageLCAT (Enzyme)bloodapo A1cholesterol extraction from cells HDL carries CE for liver clearance (to bile acids)CERPplasma membraneapo A1 (choles.Induced)flips cholesterol (and lecithin) to outer layer of lipid bilayer for LCAT action in bloodTTPintestine/liversmooth ERnoneloads TAGs onto B48 (gut) and B100 (liver)Apo A1blood, plasma membranenoneactivates LCAT and CERP; binds to apo A1 receptors on cells requiring cholesterol extractionApo B48Gutnoneexport of chylomicrons from intestinal cellsApo B100Various cellsnoneligand for LDL receptor; export of liver VLDLApo CIIcapillary wallsnoneactivates lipoprotein lipaseApo Elivernonereceptor ligand - clears remnants, IDL, and HDL