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.