High density lipoprotein metabolism in low density lipoprotein receptor-deficient mice

Michael Hayden,Joerg Heeren,Rajasekhar Ramakrishnan,May Brundert,Roshni Singaraja,Franz Rinninger,Markus Heine

doi:10.1194/jlr.m048819

Abstract

The LDL receptor (LDLR) and scavenger receptor class B type I (SR-BI) play physiological roles in LDL and HDL metabolism in vivo. In this study, we explored HDL metabolism in LDLR-deficient mice in comparison with WT littermates. Murine HDL was radiolabeled in the protein ((125)I) and in the cholesteryl ester (CE) moiety ([(3)H]). The metabolism of (125)I-/[(3)H]HDL was investigated in plasma and in tissues of mice and in murine hepatocytes. In WT mice, liver and adrenals selectively take up HDL-associated CE ([(3)H]). In contrast, in LDLR(-/-) mice, selective HDL CE uptake is significantly reduced in liver and adrenals. In hepatocytes isolated from LDLR(-/-) mice, selective HDL CE uptake is substantially diminished compared with WT liver cells. Hepatic and adrenal protein expression of lipoprotein receptors SR-BI, cluster of differentiation 36 (CD36), and LDL receptor-related protein 1 (LRP1) was analyzed by immunoblots. The respective protein levels were identical both in hepatic and adrenal membranes prepared from WT or from LDLR(-/-) mice. In summary, an LDLR deficiency substantially decreases selective HDL CE uptake by liver and adrenals. This decrease is independent from regulation of receptor proteins like SR-BI, CD36, and LRP1. Thus, LDLR expression has a substantial impact on both HDL and LDL metabolism in mice.

Highlights

The LDL receptor (LDLR) and scavenger receptor class B type I (SR-BI) play physiological roles in LDL and HDL metabolism in vivo
The compositional analysis of HDL isolated by sequential ultracentrifugation from murine plasma showed that LDLRϪ/ϪHDL is significantly enriched in triglycerides and depleted in phospholipids compared with with LDLR expression (WT)-HDL (Table 2)
We found a minor increase in plasma HDL cholesterol in male LDLRϪ/Ϫ mice compared with WT littermates, this difference was not statistically significant

Summary

Introduction

The LDL receptor (LDLR) and scavenger receptor class B type I (SR-BI) play physiological roles in LDL and HDL metabolism in vivo. We explored HDL metabolism in LDLR-deficient mice in comparison with WT littermates. In WT mice, liver and adrenals selectively take up HDL-associated CE ([3H]). In LDLR؊/؊ mice, selective HDL CE uptake is significantly reduced in liver and adrenals. In hepatocytes isolated from LDLR؊/؊ mice, selective HDL CE uptake is substantially diminished compared with WT liver cells. The respective protein levels were identical both in hepatic and adrenal membranes prepared from WT or from LDLR؊/؊ mice. An LDLR deficiency substantially decreases selective HDL CE uptake by liver and adrenals. This decrease is independent from regulation of receptor proteins like SR-BI, CD36, and LRP1. LDLR expression has a substantial impact on both HDL and LDL metabolism in mice.—Rinninger, F., M.

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Results

Conclusion