Metabolism of lipoproteins containing apolipoprotein B in hepatic lipase-deficient mice

Shiqiang Qiu,Nathalie Bergeron,Leila Kotite,Ronald M Krauss,Andre Bensadoun,Richard J Havel

doi:10.1016/s0022-2275(20)32196-9

Abstract

Mice lacking hepatic lipase have been reported to express mild hyperlipidemia characterized by increased concentrations of large high density lipoproteins, but normal concentrations of lipoproteins containing apolipoprotein B. Whereas hepatic lipase has been implicated in the clearance and processing of chylomicron remnants in rats, no such defect was found in these mice. We have further characterized the abnormal lipoprotein phenotype in young hepatic lipase-deficient mice and have found more pronounced elevations of high density lipoproteins associated in particular with a 5-fold increase in plasma concentrations of apolipoprotein E. In addition, there was a reduction in the concentration of low density lipoproteins containing apolipoprotein B-100 and B-48 relative to precursor lipoproteins of lower density and a pronounced deficiency of apolipoprotein B-containing low density lipoproteins with density exceeding 1.029 g/mL. Conversion of radiolabeled rabbit intermediate density lipoproteins to low density lipoproteins was reduced by 6-fold as compared with wild-type mice. Although clearance of cholesteryl ester-labeled chylomicrons from the blood was unimpaired in the deficient mice, that of chylomicron remnants was reduced. Furthermore, endocytosis of chylomicron cholesteryl esters into liver cells occurred more rapidly than in wild-type mice. The unimpaired hepatic clearance of injected chylomicron particles in hepatic lipase-deficient mice may be the result of greater acquisition of apoE from high density lipoproteins during remnant formation.▪ These studies thus demonstrate a critical role for mouse hepatic lipase in the formation of small, dense low density lipoproteins, as well as participation in the normal clearance and processing of chylomicron remnants.—Qiu, S., N. Bergeron, L. Kotite, R. M. Krauss, A. Bensadoun, and R. J. Havel. Metabolism of lipoproteins containing apolipoprotein B in hepatic lipase-deficient mice.

Highlights

Mice lacking hepatic lipase have been reported to express mild hyperlipidemia characterized by increased concentrations of large high density lipoproteins, but normal concentrations of lipoproteins containing apolipoprotein B
We found higher concentrations of apoB-100 and B-48 in very low density lipoproteins (VLDL) and intermediate density lipoproteins (IDL) and reduced concentrations in low density lipoproteins (LDL) of our hepatic lipase (HL) (Ϫ/Ϫ) female mice, as well as increased concentrations of these proteins in VLDL and IDL relative to LDL in mutant animals of both sexes
These observations, which suggest a defect in conversion of IDL containing either apoB-48 or apoB-100 to LDL in the mutants, are strongly supported by the virtual absence of LDL species smaller than 271 Å in peak diameter in the mutants, whereas they comprised an appreciable fraction of wild-type LDL species

Summary

Introduction

Mice lacking hepatic lipase have been reported to express mild hyperlipidemia characterized by increased concentrations of large high density lipoproteins, but normal concentrations of lipoproteins containing apolipoprotein B. We have further characterized the abnormal lipoprotein phenotype in young hepatic lipase-deficient mice and have found more pronounced elevations of high density lipoproteins associated in particular with a 5-fold increase in plasma concentrations of apolipoprotein E. The unimpaired hepatic clearance of injected chylomicron particles in hepatic lipase-deficient mice may be the result of greater acquisition of apoE from high density lipoproteins during remnant formation. These studies demonstrate a critical role for mouse hepatic lipase in the formation of small, dense low density lipoproteins, as well as participation in the normal clearance and processing of chylomicron remnants.—Qiu, S., N.

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