Features of cholesterol structure that regulate the clearance of chylomicron-like lipid emulsions.
Cholesterol is an absolute requirement for the clearance from plasma of the remnants of triglyceride-rich lipoproteins. Our laboratory previously established that cholesterol was essential for the hepatic uptake of remnant particles after intravenous injection of chylomicron-like lipid emulsions (1). The aim of the present study was to determine the structural features of the cholesterol molecule that regulate the metabolism of chylomicrons. Chylomicron-like lipid emulsions, which reflect the size and composition and mimic the physiology of lymph chylomicrons, were prepared with tracer amounts of labeled triolein ([14C]TO) and cholesteryl oleate ([3H]CO) to follow the hydrolysis of triglyceride and the uptake of chylomicron remnant particles by the liver. Sterols selected as cholesterol congeners with functional group variations were incorporated into the emulsions in place of cholesterol and injected intravenously in rats. Control emulsions contained either no cholesterol or approximately 1% (by weight) cholesterol. The effects of the different sterol structures on lipolysis and hepatic remnant uptake were compared with controls to determine the significance of various functional groups. Clearance of emulsion CO was impaired when cholesterol was absent or replaced by cholesteryl chloride, cholesteryl formate, or 3-keto-cholesterol. Clearance of emulsions containing epicholesterol, where the OH group at the 3-position is in the alpha configuration, was similar to control emulsions containing cholesterol. Congeners with an additional hydroxyl group, viz. 7 alpha-hydroxycholesterol, 7 beta-hydroxycholesterol, or 25-hydroxycholesterol, reduced CO clearance. Androstenol, which lacks the side chain at the C17-position, also retarded CO clearance from plasma. In contrast, emulsions incorporating congeners with side chain variations such as campesterol, beta-sitosterol, stigmasterol, or saturated congeners of cholesterol such as cholestanol, coprostanol and its epimer, epicoprostanol, all were cleared similarly to emulsions containing cholesterol. In conclusion, for physiological clearance of a chylomicron-like emulsion, the presence of a hydroxyl (-OH) group at the 3-position and an alkyl side chain at the C17-position of cholesterol are essential, while the structure of the side chain and the saturation of the ring structure are not critical. The mechanism of the specificity of sterols on the metabolism of protein-free emulsions is unclear, but does not relate to changes in microfluidity of the surface lipids, nor to the amount or isoform of associated apolipoproteins.
Mortimer
B C
BC
Department of Physiology, University of Western Australia, Nedlands, Australia.
Tso
P
P
Phan
C T
CT
Beveridge
D J
DJ
Wen
J
J
Redgrave
T G
TG
D000818:Animals; D001057:Apolipoproteins E / Q000097:blood; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism; D002914:Chylomicrons / Q000378:metabolism*; D004655:Emulsions / Q000737:chemistry / Q000378:metabolism*; D006900:Hydroxylation; D007700:Kinetics; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008657:Metabolic Clearance Rate; D008854:Microscopy, Electron; D010316:Particle Size; D051381:Rats; D017208:Rats, Wistar; D013050:Spectrometry, Fluorescence
D001057:Apolipoproteins E; D002914:Chylomicrons; D004655:Emulsions; D002784:Cholesterol