Hepatic ABCA1 deficiency is associated with delayed apolipoprotein B secretory trafficking and augmented VLDL triglyceride secretion

Mingxia Liu, Soonkyu Chung, Gregory S. Shelness, John S. Parks

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

ATP binding cassette transporter A1 (ABCA1) is a membrane transporter that facilitates nascent HDL formation. Tangier disease subjects with complete ABCA1 deficiency have < 5% of normal levels of plasma HDL, elevated triglycerides (TGs), and defective vesicular trafficking in fibroblasts and macrophages. Hepatocyte-specific ABCA1 knockout mice (HSKO) have a similar lipid phenotype with 20% of normal plasma HDL levels and a two-fold elevation of plasma TGs due to hepatic overproduction of large, triglyceride-enriched VLDL. We hypothesized that enhanced VLDL TG secretion in the absence of hepatocyte ABCA1 is due to altered intracellular trafficking of apolipoprotein B (apoB), resulting in augmented TG addition to nascent VLDL. We found that trafficking of newly synthesized apoB through the secretory pathway was delayed in ABCA1-silenced rat hepatoma cells and HSKO primary hepatocytes, relative to controls. Endoglycosidase H treatment of cellular apoB revealed a likely delay in apoB trafficking in post-ER compartments. The reduced rate of protein trafficking was also observed for an adenoviral-expressed GPI-linked fluorescent fusion protein, but not albumin, suggesting a selective delay of secretory cargoes in the absence of hepatocyte ABCA1. Our results suggest an important role for hepatic ABCA1 in regulating secretory trafficking and modulating VLDL expansion during the TG accretion phase of hepatic lipoprotein particle assembly.

Original languageEnglish (US)
Pages (from-to)1035-1043
Number of pages9
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Volume1862
Issue number10
DOIs
StatePublished - Oct 2017

Keywords

  • Endoplasmic reticulum
  • Golgi apparatus
  • HDL deficiency
  • VLDL1
  • Vesicular trafficking

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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