title: Hepatic ABCA1 and VLDL triglyceride production.
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.
authors: Department of Pathology/Section on Lipid Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors: Mingxia
authors: M
authors: Liu
authors: Soonkyu
authors: S
authors: Chung
authors: Gregory S
authors: GS
authors: Shelness
authors: John S
authors: JS
authors: Parks
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D024821:Metabolic Syndrome / Q000378:metabolism; D051379:Mice; D013631:Tangier Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood*
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D014280:Triglycerides