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- W2183519042 abstract "Molecular mechanisms regulating thebind- ing, amphipathic stabilization, andmetabolism ofthemajor neutral lipids (e.g., cholesteryl esters, triglycerides, andfatty acids) arewell studied, butthedetails oftheir movement from abinding compartment toametabolic compartment deserve further attention. Since allneutral lipids mustcross hydro- philic segments ofplasma membranes during suchmovement, wepostulate thata critical receptor-like site exists onthe plasma membranetomediate a stepbetween binding and metabolism andthatmembrane-associated heparin isakey partofthis mediator. Forexample, intestinal brushborder membranes containing heparin bindhomogeneous human pancreatic MI-labeled cholesterol esterase (100 kDa)and1251- labeled triglyceride lipase (52kDa). Thisinteraction isenzyme concentration-dependent, specific, andsaturable andisre- versed uponaddition ofsoluble heparin. Scatchard analysis demonstrates asingle class ofreceptors with aKdof100nMand aBmaxof approximately 50-60pmolpermgofvesicle protein. Incontrast, enzymes associated withthehydrolysis ofhydro- philic compounds suchasamylase, phospholipase A2,and deoxyribonuclease donotbindtointestinal membranes inthis manner.Humanpancreatic cholesterol esterase alsobinds specifically andsaturably tocultured intestinal epithelial cells (CaCo-2), andsoluble heparin significantly diminishes the cellular uptake oftheresultant hydrophobic reaction products (cholesterol andfree fatty acids). Weconclude that aphysio- logical role forintestinal heparin isthat ofamediator tobind neutral lipolytic enzymes atthebrush border andthus promote absorption ofthesubsequent hydrolyzed nutrients inthe intestine. Thismechanism maybeageneralizable pathway for transport ofneutral lipids into endothelial andother cells. Neutral lipids suchascholesterol esters andtriglycerides mustmoveintocells fromanaqueousmilieu, yetthese compounds areinsoluble inwaterandessentially lack deter- gentproperties. Theyentervarious intracellular pools from a variety ofstabilized structures. Neutral lipids canbe surrounded byahydrophilic shell composed ofphospholipids orserumlipoproteins, theycanbeencompassed bydeter- gents andphospholipids (intestinal micelles), orthey canbe boundtoamphipathic proteins (transfer proteins). A central biological conundrum hasbeenthemolecular basesof movementoftheselipids intocells fromsuchorganized structures acrossthehydrophilic segmentoftheplasma membrane. Forexample, dietary lipid ingested asthefatty acidesterofcholesterol orofglycerol mustbehydrolyzed before intestinal absorption canoccur(1). Hydrolysis pro- duces veryhydrophobic compounds inanaqueous environ- ment,and,currently, no cohesive hypothesis exists to explain transport ofthese molecules through anunstirred water layer andacross thehydrophilic outer leaflet ofthe absorptive membrane after egress frommicellar structures. Therefore, we postulate thata molecular mediator of amphipathic nature mustexist tofacilitate juxtaposition of these hydrophobic lipids withthehydrophilic outer plasma membrane underconditions whereoperation ofreceptor- mediated endocytosis maybelimited. Forexample, this type oftransport mayberequired fortheinternalization ofneutral lipids fromtheintestinal lumenwherelipoproteins arenot present. Homogeneous humanpancreatic cholesterol ester- asebinds reversibly tomembrane heparin invitro (C.A.S. andL.G.L., unpublished data), andthusthehighconcen- tration ofheparin intheintestine could serve toconcentrate andlocalize neutral lipolytic enzymesontheintestinal membrane. Thisanchoring mechanism wouldfacilitate theabsorption ofneutral lipids fromanunfavorable aqueous milieu by allowing theproduction ofsubcritical micelle concentrations ofhydrophobic reaction products attheenterocyte mem- brane. Because ofthegeneral nature ofthis problem, the ubiquitous presence ofheparin-like molecules inplasma membranes andtheknownaffinities ofother keyneutral lipolytic enzymesorbinding proteins forheparin (e.g., lipoprotein lipase (3)andlow-density lipoprotein (LDL)(4)), wepostulate that amajor physiological role ofheparin isto function asamediator forfacilitating movement ofneutral lipids into cells ofmanytypes." @default.
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- W2183519042 date "1988-01-01" @default.
- W2183519042 modified "2023-09-27" @default.
- W2183519042 title "Receptor-like function ofheparin inthebinding anduptakeof neutral lipids (glycosaminoglycans/atherogenesis/cholesterol" @default.
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