TY - JOUR
T1 - Hepatic ABCA1 deficiency is associated with delayed apolipoprotein B secretory trafficking and augmented VLDL triglyceride secretion
AU - Liu, Mingxia
AU - Chung, Soonkyu
AU - Shelness, Gregory S.
AU - Parks, John S.
N1 - Funding Information:
We gratefully acknowledge the editorial assistance of Karen Klein, MA, in the Wake Forest Clinical and Translational Science Institute (UL1 TR001420; PI: McClain) and Drs. Ruth McPherson (University of Ottawa) and Kai Simons (Max Planck Institute) for supplying adenovirus YFP-GPI. This project was supported by National Institutes of Health Grants (P01HL49373 to [JSP & GSS] and R01HL119962 to JSP) and American Heart Association Pre-doctoral Fellowship (12PRE12040309 to ML) and RJR-Leon Golberg Post-doctoral Fellowship to ML. This article was prepared while Gregory S. Shelness was employed by Wake Forest School of Medicine. The opinions expressed in this article are the authors' own and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government.
PY - 2017/10
Y1 - 2017/10
N2 - 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.
AB - 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.
KW - Endoplasmic reticulum
KW - Golgi apparatus
KW - HDL deficiency
KW - VLDL1
KW - Vesicular trafficking
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U2 - 10.1016/j.bbalip.2017.07.001
DO - 10.1016/j.bbalip.2017.07.001
M3 - Article
C2 - 28694219
AN - SCOPUS:85024374921
VL - 1862
SP - 1035
EP - 1043
JO - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
JF - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
SN - 1388-1981
IS - 10
ER -