Nonalcoholic steatohepatitis (NASH) is the progressive form of
nonalcoholic fatty liver disease and is one of the most common
liver diseases in the developed world. The histological findings of NASH are characterized by hepatic steatosis,
inflammation, and
fibrosis. However, an optimal treatment for NASH has not been established.
Tranilast, N-(3',4'-dimethoxycinnamoyl)-anthranilic
acid, is an antifibrogenic agent that inhibits the action of
transforming growth factor beta (
TGF-beta). This
drug is used clinically for fibrogenesis-associated skin disorders including
hypertrophic scars and scleroderma.
TGF-beta plays a central role in the development of hepatic
fibrosis, and
tranilast may thus ameliorate the pathogenesis of NASH. We investigated the effects of
tranilast using an established dietary animal model of NASH, obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and nondiabetic control Long-Evans Tokushima Otsuka (LETO) rats fed a
methionine-deficient and
choline-deficient diet. Treatment with 2%
tranilast (420 mg/kg/day) for 8 weeks prevented the development of hepatic
fibrosis and the activation of stellate cells, and down-regulated the expression of genes for
TGF-beta and
TGF-beta-target molecules, including alpha1
procollagen and
plasminogen activator-1. In addition,
tranilast attenuated hepatic
inflammation and Kupffer cell recruitment, and down-regulated the expression of
tumor necrosis factor alpha. Unexpectedly,
tranilast ameliorated hepatic steatosis and up-regulated the expression of genes involved in beta-oxidation, such as
peroxisome proliferator-activated receptor alpha and
carnitine O-palmitoyltransferase-1. Most of these effects were observed in LETO rats and OLETF rats, which suggest that the action of
tranilast is mediated through the
insulin resistance-independent pathway.
CONCLUSION: