Pentoxifylline attenuates steatohepatitis induced by the methionine choline deficient diet.
OBJECTIVE
Feeding mice a methionine choline deficient (MCD) diet serves as a nutritional model of non-alcoholic steatohepatitis (NASH). NASH and alcohol-induced steatohepatitis are histologically similar, suggesting a similar pathogenesis. Pentoxifylline (PTX) attenuates TNF-alpha production, acts as an antioxidant and decreases mortality in alcoholic steatohepatitis. The aim of our study is to determine if PTX attenuates MCD diet induced steatohepatitis and determine the mechanism of this effect.


METHODS
Mice were placed on an MCD or control diet for 2 weeks and were treated with or without PTX. Serum ALT, liver histology, and inflammatory mechanisms were evaluated.


RESULTS
PTX attenuates MCD diet induced steatohepatitis, decreasing both serum ALT levels and hepatic inflammation. Serum ALT levels were reduced approximately 50% in the MCD+PTX group compared to the MCD group. Hepatic glutathione levels were significantly higher in the MCD+PTX group compared to the MCD group. There was also a reduction in TNF-alpha mRNA in female mice treated with PTX. MCD+PTX mice had increased hepatic triglyceride content compared to the MCD mice, but less histologic evidence of inflammation despite the increased steatosis. Serum lipid and bile salt levels also were similar in PTX and vehicle control treated mice.


CONCLUSIONS
PTX decreases serum ALT levels and hepatic inflammation in the MCD model of steatohepatitis, likely via increasing glutathione levels or reducing TNF-alpha expression.
Department of Medicine, Division of Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Sean W P
SW
Koppe
Atul
A
Sahai
Padmini
P
Malladi
Peter F
PF
Whitington
Richard M
RM
Green
D000410:Alanine Transaminase / Q000037:antagonists & inhibitors / Q000097:blood; D000818:Animals; D002796:Choline Deficiency / Q000150:complications*; D003677:Deficiency Diseases / Q000150:complications; D004032:Diet; D018450:Disease Progression; D005234:Fatty Liver / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006505:Hepatitis / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D010431:Pentoxifylline / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000037:antagonists & inhibitors; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D010726:Phosphodiesterase Inhibitors; D012333:RNA, Messenger; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D008715:Methionine; D000410:Alanine Transaminase; D005978:Glutathione; D010431:Pentoxifylline