Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis.
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.
Marí
Montserrat
M
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.
Caballero
Francisco
F
Colell
Anna
A
Morales
Albert
A
Caballeria
Juan
J
Fernandez
Anna
A
Enrich
Carlos
C
Fernandez-Checa
José C
JC
García-Ruiz
Carmen
C
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
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