Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis

Cell Metab. 2006 Sep;4(3):185-98. doi: 10.1016/j.cmet.2006.07.006.

Abstract

The etiology of progression from steatosis to steatohepatitis (SH) remains unknown. Using nutritional and genetic models of hepatic steatosis, we show that free cholesterol (FC) loading, but not free fatty acids or triglycerides, sensitizes to TNF- and Fas-induced SH. FC distribution in endoplasmic reticulum (ER) and plasma membrane did not cause ER stress or alter TNF signaling. Rather, mitochondrial FC loading accounted for the hepatocellular sensitivity to TNF due to mitochondrial glutathione (mGSH) depletion. Selective mGSH depletion in primary hepatocytes recapitulated the susceptibility to TNF and Fas seen in FC-loaded hepatocytes; its repletion rescued FC-loaded livers from TNF-mediated SH. Moreover, hepatocytes from mice lacking NPC1, a late endosomal cholesterol trafficking protein, or from obese ob/ob mice, exhibited mitochondrial FC accumulation, mGSH depletion, and susceptibility to TNF. Thus, we propose a critical role for mitochondrial FC loading in precipitating SH, by sensitizing hepatocytes to TNF and Fas through mGSH depletion.

Publication types

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

MeSH terms

  • Animals
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Cells, Cultured
  • Cholesterol / metabolism*
  • Cholesterol / pharmacology
  • Disease Models, Animal
  • Disease Progression
  • Fatty Liver / chemically induced
  • Fatty Liver / metabolism*
  • Fatty Liver / physiopathology
  • Glutathione / deficiency*
  • Hepatitis / metabolism*
  • Hepatitis / physiopathology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Intracellular Signaling Peptides and Proteins
  • Liver / metabolism*
  • Liver / physiopathology
  • Male
  • Mice
  • Mice, Transgenic
  • Mitochondria / metabolism*
  • Mitochondrial Membranes / drug effects
  • Mitochondrial Membranes / metabolism
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology
  • Proteins / genetics
  • Proteins / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Tumor Necrosis Factor-alpha / metabolism
  • Tumor Necrosis Factor-alpha / pharmacology
  • fas Receptor / metabolism
  • fas Receptor / pharmacology

Substances

  • Intracellular Signaling Peptides and Proteins
  • Npc1 protein, mouse
  • Proteins
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Cholesterol
  • Glutathione