Tranilast, an antifibrogenic agent, ameliorates a dietary rat model of nonalcoholic steatohepatitis.
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.


CONCLUSIONS
Our findings suggest that targeting TGF-beta with tranilast represents a new mode of therapy for NASH.
Uno
Masafumi
M
Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Kurita
Seiichiro
S
Misu
Hirofumi
H
Ando
Hitoshi
H
Ota
Tsuguhito
T
Matsuzawa-Nagata
Naoto
N
Kita
Yuki
Y
Nabemoto
Satoko
S
Akahori
Hiroshi
H
Zen
Yoh
Y
Nakanuma
Yasuni
Y
Kaneko
Shuichi
S
Takamura
Toshinari
T
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D002460:Cell Line; D002796:Choline Deficiency; D004032:Diet; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000150:complications / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D015850:Interleukin-6 / Q000096:biosynthesis; D007728:Kupffer Cells / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000209:etiology / Q000517:prevention & control*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008715:Methionine / Q000172:deficiency; D010084:Oxidation-Reduction / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D015854:Up-Regulation; D062367:ortho-Aminobenzoates / Q000494:pharmacology*; D000093242:Interleukin-6 Inhibitors
D002334:Carnitine O-Palmitoyltransferase; D005227:Fatty Acids; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008715:Methionine; D047493:PPAR alpha; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D062367:ortho-Aminobenzoates; D000093242:Interleukin-6 Inhibitors; C012293:tranilast