Harpers

210 / CHAPTER 25NascentVLDLB-100ELDL(apo B-100, E)receptorTGCCEApo C, Apo EAPC CEVLDLB-100TGCCEXTRAHEPATICTISSUESFatty acidsHDLApo CLIPOPROTEIN LIPASEB-100CholesterolLIVERFinal destruction inliver, extrahepatictissues (eg, lymphocytes,fibroblasts)via endocytosisLDL(apo B-100, E)receptor?B-100CLDLTGCEIDL(VLDL remnant)EXTRAHEPATICTISSUESGlycerolFatty acidsFigure 25–4. Metabolic fate of very low density lipoproteins (VLDL) and production of low-densitylipoproteins (LDL). (A, apolipoprotein A; B-100, apolipoprotein B-100; C , apolipoprotein C; E, apolipoproteinE; HDL, high-density lipoprotein; TG, triacylglycerol; IDL, intermediate-density lipoprotein; C, cholesterol andcholesteryl ester; P, phospholipid.) Only the predominant lipids are shown. It is possible that some IDL is alsometabolized via the LRP.lysolecithin (Chapter 24). The nonpolar cholesteryl estersmove into the hydrophobic interior of the bilayer,whereas lysolecithin is transferred to plasma albumin.Thus, a nonpolar core is generated, forming a spherical,pseudomicellar HDL covered by a surface film of polarlipids and apolipoproteins. In this way, the LCAT systemis involved in the removal of excess unesterifiedcholesterol from lipoproteins and tissues. The class Bscavenger receptor B1 (SR-B1) has recently beenidentified as an HDL receptor in the liver and insteroidogenic tissues. HDL binds to the receptor viaapo A-I and cholesteryl ester is selectively delivered tothe cells, but the particle itself, including apo A-I, is nottaken up. The transport of cholesterol from the tissuesto the liver is known as reverse cholesterol transportand is mediated by an HDL cycle (Figure 25–5). Thesmaller HDL 3 accepts cholesterol from the tissues viathe ATP-binding cassette transporter-1 (ABC-1).ABC-1 is a member of a family of transporter proteinsthat couple the hydrolysis of ATP to the binding of asubstrate, enabling it to be transported across the membrane.After being accepted by HDL 3 , the cholesterol isthen esterified by LCAT, increasing the size of the particlesto form the less dense HDL 2 . The cycle is completedby the re-formation of HDL 3 , either after selectivedelivery of cholesteryl ester to the liver via theSR-B1 or by hydrolysis of HDL 2 phospholipid and triacylglycerolby hepatic lipase. In addition, free apo A-Iis released by these processes and forms pre-HDLafter associating with a minimum amount of phospholipidand cholesterol. Preβ-HDL is the most potentform of HDL in inducing cholesterol efflux from thetissues to form discoidal HDL. Surplus apo A-I is destroyedin the kidney.HDL concentrations vary reciprocally with plasmatriacylglycerol concentrations and directly with the activityof lipoprotein lipase. This may be due to surplussurface constituents, eg, phospholipid and apo A-Ibeing released during hydrolysis of chylomicrons andVLDL and contributing toward the formation of preβ-HDL and discoidal HDL. HDL 2 concentrations are inverselyrelated to the incidence of coronary atherosclerosis,possibly because they reflect the efficiency ofreverse cholesterol transport. HDL c (HDL 1 ) is found in