SR-BI-mediated selective lipid uptake segregates apoA-I and apoA-II catabolism

Maria C De Beer,Deneys Van Der Westhuyzen,Nathan L Whitaker,Nancy R Webb,Frederick C De Beer

doi:10.1194/jlr.m500068-jlr200

Maria C De Beer, Deneys Van Der Westhuyzen + Show 3 more

Open Access

https://doi.org/10.1194/jlr.m500068-jlr200

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Abstract

The HDL receptor scavenger receptor class B type I (SR-BI) binds HDL and mediates the selective uptake of cholesteryl ester. We previously showed that remnants, produced when human HDL(2) is catabolized in mice overexpressing SR-BI, become incrementally smaller, ultimately consisting of small alpha-migrating particles, distinct from pre-beta HDL. When mixed with mouse plasma, some remnant particles rapidly increase in size by associating with HDL without the mediation of cholesteryl ester transfer protein, LCAT, or phospholipid transfer protein. Here, we show that processing of HDL(2) by SR-BI-overexpressing mice resulted in the preferential loss of apolipoprotein A-II (apoA-II). Short-term processing generated two distinct, small alpha-migrating particles. One particle (8.0 nm diameter) contained apoA-I and apoA-II; the other particle (7.7 nm diameter) contained only apoA-I. With extensive SR-BI processing, only the 7.7 nm particle remained. Only the 8.0 nm remnants were able to associate with HDL. Compared with HDL(2), this remnant was more readily taken up by the liver than by the kidney. We conclude that SR-BI-generated HDL remnants consist of particles with or without apoA-II and that only those containing apoA-II associate with HDL in an enzyme-independent manner. Extensive SR-BI processing generates small apoA-II-depleted particles unable to reassociate with HDL and readily taken up by the liver. This represents a pathway by which apoA-I and apoA-II catabolism are segregated.

Highlights

The HDL receptor scavenger receptor class B type I (SR-BI) binds HDL and mediates the selective uptake of cholesteryl ester
Given the influence of apolipoprotein A-II (apoA-II) on HDL metabolism and HDL/SR-BI interaction, we investigated the role of apoA-II on the generation and subsequent remodeling of HDL remnants
A bolus of 750 ␮g of HDL2 traced with 125I was injected into the mice, and plasma samples were collected for analysis at selected intervals after bolus injection

Summary

Introduction

The HDL receptor scavenger receptor class B type I (SR-BI) binds HDL and mediates the selective uptake of cholesteryl ester. Data indicated a segregation of apoA-I and apoA-II into distinct remnant particles, such that extensive processing by SR-BI yielded a small ␣-migrating HDL remnant containing apoA-I only that was resistant to remodeling by failing to associate with larger HDLs. When injected into normal C57BL/6 mice, these apoA-I-only remnant particles exhibited enhanced uptake into the liver compared with unmodified HDL2. As we have reported previously, HDL remnants that have accumulated in apoA-IϪ/Ϫ mice 3 h after bolus injection are too dense to refloat from plasma by density ultracentrifugation [2].

Results

Conclusion