We have proposed that
steatohepatitis results from
reactive oxygen species (ROS) acting on accumulated
fatty acids to form proinflammatory
lipoperoxides.
Cytochrome P450 4a (
Cyp4a) and
Cyp2e1 are potential hepatic sources of ROS. We tested the hypothesis that increasing
Cyp4a through activation of
peroxisome proliferator-activated receptor alpha (
PPARalpha) should aggravate
steatohepatitis produced by feeding a
methionine and
choline deficient (MCD) diet. Conversely, we assessed dietary
steatohepatitis in
PPARalpha(-/-) mice that cannot up-regulate
Cyp4a. Male wild type (wt) or
PPARalpha(-/-) mice (C57BL6 background) were fed the MCD diet with or without
Wy-14,643 (0.1% wt/wt), a potent
PPARalpha agonist. Controls were fed the same diet supplemented with
methionine and
choline. After 5 weeks, wt mice fed the MCD diet developed moderate
steatohepatitis and
alanine aminotransferase (ALT) levels were increased.
Wy-14,643 prevented rather than increased liver injury; ALT levels were only mildly elevated whereas
steatohepatitis was absent.
Wy-14,643 up-regulated
mRNA for
liver fatty acid binding protein and peroxisomal beta-oxidation
enzymes (
acyl-CoA oxidase, bifunctional
enzyme, and ketothiolase), thereby reducing hepatic
triglycerides and preventing steatosis. In wt mice, dietary feeding up-regulated Cyp4a14
mRNA 2.7-fold and increased hepatic
lipoperoxides compared with controls.
Wy-14,643 prevented hepatic
lipoperoxides from accumulating despite an 18-fold increase in both Cyp4a10 and Cyp4a14
mRNA.
PPARalpha(-/-) mice fed the MCD diet developed more severe
steatohepatitis than wt mice, and were unaffected by
Wy-14,643. In conclusion,
PPARalpha activation both increases
Cyp4a expression and enhances hepatic
lipid turnover; the latter effect removes
fatty acids as substrate for lipid peroxidation and is sufficiently powerful to prevent the development of dietary
steatohepatitis.