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

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          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.

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          Author and article information

          Journal
          Cell Metab
          Cell metabolism
          Elsevier BV
          1550-4131
          1550-4131
          Sep 2006
          : 4
          : 3
          Affiliations
          [1 ] Liver Unit, Institut de Malalties Digestives, Hospital Clínic i Provincial, Instituto Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Consejo Superior de Investigaciones Científicas, Barcelona, Spain.
          Article
          S1550-4131(06)00265-8
          10.1016/j.cmet.2006.07.006
          16950136
          8a5a3f38-6c51-423a-9774-aacd9dcce565

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