Enhanced sensitivity to CD95-induced apoptosis in ob/ob mice.
Hepatocyte apoptosis was recently described for NASH patients. The pathomechanisms are incompletely understood, but upregulation of the death receptor Fas was detectable on hepatocytes of NASH patients. We analyzed the sensitivity of fatty liver against CD95/Fas-mediated apoptotic cell death by injection of agonistic anti-Fas antibody (Jo2) in obese ob/ob mice and lean control animals. Ob/ob mice died within 12 hrs, whereas control animals survived. Liver enzymes were significantly increased compared to those in control mice (P < 0.001). Histological analysis and also TUNEL assay of liver sections from ob/ob mice exhibited massive liver injury. Activity of caspase 3 was significantly more enhanced in livers of ob/ob mice after Jo2 challenge. The increased sensitivity was confirmed in vitro by using ob/ob-derived primary hepatocytes. CD95 expression was similar in ob/ob and control mice. However, hepatocytes from ob/ob mice revealed a decreased mitochondrial membrane potential, suggesting that mitochondria play a potential role in this increased susceptibility.
Siebler
Juergen
J
Department of Medicine, University of Mainz, Langenbeckstr. 1, 55131 Mainz, Germany. siebler@uni-mainz.de
Schuchmann
Markus
M
Strand
Susanne
S
Lehr
Hans A
HA
Neurath
Markus F
MF
Galle
Peter R
PR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D005234:Fatty Liver / Q000139:chemically induced / Q000401:mortality / Q000473:pathology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020287:In Situ Nick-End Labeling; D020738:Leptin / Q000172:deficiency; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D012720:Severity of Illness Index; D015996:Survival Rate; D019014:fas Receptor / Q000096:biosynthesis / Q000276:immunology* / Q000633:toxicity
D020738:Leptin; D019014:fas Receptor; D020169:Caspases