title: Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis.
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.
authors.affiliation: 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.
authors.forename: Montserrat
authors.initials: M
authors.lastname: Marí
authors.forename: Francisco
authors.initials: F
authors.lastname: Caballero
authors.forename: Anna
authors.initials: A
authors.lastname: Colell
authors.forename: Albert
authors.initials: A
authors.lastname: Morales
authors.forename: Juan
authors.initials: J
authors.lastname: Caballeria
authors.forename: Anna
authors.initials: A
authors.lastname: Fernandez
authors.forename: Carlos
authors.initials: C
authors.lastname: Enrich
authors.forename: José C
authors.initials: JC
authors.lastname: Fernandez-Checa
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Ruiz
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism* / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D005978:Glutathione / Q000172:deficiency*; D006505:Hepatitis / Q000378:metabolism* / Q000503:physiopathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D019014:fas Receptor / Q000378:metabolism / Q000494:pharmacology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D002784:Cholesterol; D005978:Glutathione