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Review
. 2012 May;1821(5):770-7.
doi: 10.1016/j.bbalip.2011.09.020. Epub 2011 Oct 6.

Hepatic ABCA1 and VLDL triglyceride production

Mingxia Liu  1 , Soonkyu Chung, Gregory S Shelness, John S Parks
Affiliations
Review

Hepatic ABCA1 and VLDL triglyceride production

Mingxia Liu et al. Biochim Biophys Acta. 2012 May.

Abstract

Elevated plasma triglyceride (TG) and reduced high density lipoprotein (HDL) concentrations are prominent features of metabolic syndrome (MS) and type 2 diabetes (T2D). Individuals with Tangier disease also have elevated plasma TG concentrations and a near absence of HDL, resulting from mutations in ATP binding cassette transporter A1 (ABCA1), which facilitates the efflux of cellular phospholipid and free cholesterol to assemble with apolipoprotein A-I (apoA-I), forming nascent HDL particles. In this review, we summarize studies focused on the regulation of hepatic very low density lipoprotein (VLDL) TG production, with particular attention on recent evidence connecting hepatic ABCA1 expression to VLDL, LDL, and HDL metabolism. Silencing ABCA1 in McArdle rat hepatoma cells results in diminished assembly of large (>10nm) nascent HDL particles, diminished PI3 kinase activation, and increased secretion of large, TG-enriched VLDL1 particles. Hepatocyte-specific ABCA1 knockout (HSKO) mice have a similar plasma lipid phenotype as Tangier disease subjects, with a two-fold elevation of plasma VLDL TG, 50% lower LDL, and 80% reduction in HDL concentrations. This lipid phenotype arises from increased hepatic secretion of VLDL1 particles, increased hepatic uptake of plasma LDL by the LDL receptor, elimination of nascent HDL particle assembly by the liver, and hypercatabolism of apoA-I by the kidney. These studies highlight a novel role for hepatic ABCA1 in the metabolism of all three major classes of plasma lipoproteins and provide a metabolic link between elevated TG and reduced HDL levels that are a common feature of Tangier disease, MS, and T2D. This article is part of a Special Issue entitled: Triglyceride Metabolism and Disease.

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Figures

Figure 1
Figure 1
Nascent HDL particle formation by primary hepatocytes from wild type (WT) or hepatocyte-specific ABCA1 knockout (HSKO) mice (panel A) and control or ABCA1-expressing HEK293 cells (panel B). Cells were incubated for 24h with 125I-human apoA-I and media were harvested and concentrated for fractionation by high resolution fast protein liquid chromatography. Fractions were quantified for radiolabel and values (cpm) plotted.
Figure 2
Figure 2
In the presence of active ABCA1 (left), lipid free apoA-I is secreted by hepatocytes and lipidated by hepatocyte ABCA1, forming nascent HDL particles. Large nascent HDLs (>10 nm diameter) bind to a putative receptor (Topβ, target of pre-β), which in turn stimulates PI3 kinase activation resulting in reduced lipid mobilization and secretion of normal-sized VLDL particles (i.e., VLDL2). In the absence of hepatic ABCA1 or diminished ABCA1 activity (right), newly secreted lipid-free apoA-I fails to form large nascent HDL particles. Reduced nascent HDL particle formation leads to diminished signaling through Topβ, resulting in reduced PI3 kinase activation, increased lipid mobilization, and increased secretion of larger TG-enriched VLDL particles (VLDL1). Reprinted with permission (J Lipid Res 2010;51:729–742).
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