ABCA1-dependent lipid efflux to apolipoprotein A-I mediates HDL particle formation and decreases VLDL secretion from murine hepatocytes

Abstract

High levels of expression of the ATP binding cassette transporter A1 (ABCA1) in the liver and the need to over-or underexpress hepatic ABCA1 to impact plasma HDL levels in mice suggest a major role of the liver in HDL formation and in determining circulating HDL levels. Cultured murine hepatocytes were used to examine the role of hepatic ABCA1 in mediating the lipidation of apolipoprotein A-I (apoA-I) for HDL particle formation. Exogenous apoA-I stimulated cholesterol efflux to the medium from wild-type hepatocytes, but not from ABCA1-deficient ( abca1 ؊ / ؊ ) hepatocytes. ApoA-I induced the formation of new HDL particles and enhanced the lipidation of endogenously secreted murine apoA-I in ABCA1-expressing but not abca1 ؊ / ؊ hepatocytes. ABCA1-dependent cholesterol mobilization to apoA-I increased new cholesterol synthesis, indicating depletion of the regulatory pool of hepatocyte cholesterol during HDL formation. Secretion of triacylglycerol and apoB was decreased following apoA-I incubation with ABCA1-expressing but not abca1 ؊ / ؊ hepatocytes. These results support a major role for hepatocyte ABCA1 in generating a critical pool of HDL precursor particles that enhance further HDL generation and passive cholesterol mobilization in the periphery. The results also suggest that diversion of hepatocyte cholesterol into the "reverse" cholesterol transport pathway diminishes cholesterol availability for apoB-containing lipoprotein secretion by the liver. -Sahoo, D., T. C. Trischuk, T. Chan, V. A. B. Drover, S. Ho, G. Chimini, L. B. Agellon, R. Agnihotri, G. A. Francis, and R. Lehner. ABCA1-dependent lipid efflux to apolipoprotein A-I mediates HDL particle formation and decreases VLDL secretion from murine hepatocytes.

Hepatic ABCG5/G8 overexpression reduces apoB-lipoproteins and atherosclerosis when cholesterol absorption is inhibited

“…Several published reports support the concept that depletion of a hepatic pool of cholesterol can decrease VLDL secretion (39)(40)(41)(42)(43). In some cases, reduction of hepatic cholesterol levels decreases only the number and not the cholesterol or TG content of secreted VLDL particles.…”

On the hepatic mechanism of HDL assembly by the ABCA1/apoA-I pathway

“…We essentially confirmed these findings with HepG2 cells and, in addition, demonstrated the increase of production of such particles by exogenously added apoA-I and apoA-II. Thus, the HepG2 cells have the same pathway to generate HDL as many other cells upon interaction with helical apolipoproteins, presumably dependent on ABCA1 (26).…”

MCP-1 impacts RCT by repressing ABCA1, ABCG1, and SR-BI through PI3K/Akt posttranslational regulation in HepG2 cells

“…The effl ux of cholesterol to apoA-I is the fi rst stage of biogenesis of HDL in hepatocytes ( 29 ). Several different potential cellular cholesterol effl ux pathways have been described: diffusional effl ux, ABCA1-, ABCG1-, and SR-BImediated cholesterol effl ux pathways ( 30 ).…”