Hepatitis C virus core protein decreases lipid droplet turnover: a mechanism for core-induced steatosis

J Biol Chem. 2011 Dec 9;286(49):42615-42625. doi: 10.1074/jbc.M111.285148. Epub 2011 Oct 7.

Abstract

Steatosis is a frequent complication of hepatitis C virus infection. In mice, this condition is recapitulated by the expression of a single viral protein, the nucleocapsid core. Core localizes to the surface of lipid droplets (LDs) in infected liver cells through a process dependent on host diacylglycerol acyltransferase 1 (DGAT1), an enzyme that synthesizes triglycerides in the endoplasmic reticulum. Whether DGAT1 also plays a role in core-induced steatosis is uncertain. Here, we show that mouse embryonic fibroblasts isolated from DGAT1(-/-) mice are protected from core-induced steatosis, as are livers of DGAT1(-/-) mice expressing core, demonstrating that the steatosis is DGAT1-dependent. Surprisingly, core expression did not increase DGAT1 activity or triglyceride synthesis, thus excluding the possibility that core activates DGAT1 to cause steatosis. Instead, we find that DGAT1-dependent localization of core to LDs is a prerequisite for the steatogenic properties of the core. Using biochemical and immunofluorescence microscopy techniques, we show that the turnover of lipids in core-coated droplets is decreased, providing a physiological mechanism for core-induced steatosis. Our results support a bipartite model in which core first requires DGAT1 to gain access to LDs, and then LD-localized core interferes with triglyceride turnover, thus stabilizing lipid droplets and leading to steatosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Centrifugation, Density Gradient
  • Diacylglycerol O-Acyltransferase / metabolism
  • Fatty Liver / pathology*
  • Fibroblasts / metabolism
  • Fibroblasts / virology
  • Hepacivirus / metabolism*
  • Humans
  • Lentivirus / metabolism
  • Lipids / chemistry*
  • Lipolysis
  • Mice
  • Mice, Transgenic
  • Microscopy, Fluorescence / methods
  • Plasmids / metabolism
  • Triglycerides / metabolism
  • Viral Core Proteins / chemistry
  • Viral Core Proteins / physiology*

Substances

  • Lipids
  • Triglycerides
  • Viral Core Proteins
  • nucleocapsid protein, Hepatitis C virus
  • Dgat1 protein, mouse
  • Diacylglycerol O-Acyltransferase