Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis.
OBJECTIVE
The increasing prevalence of nonalcoholic steatohepatitis (NASH) is due to the epidemic of obesity and type 2 diabetes, both of which are associated with insulin resistance.


METHODS
To clarify the causal relationship between insulin resistance and the development of NASH, steatohepatitis was induced in obese diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) and nondiabetic control Long-Evans Tokushima Otsuka (LETO) rats by feeding them a methionine and choline-deficient (MCD) diet. Insulin sensitivity of the rats was altered by adding a high-fat (HF) diet or the peroxisomal-proliferator activated receptor-gamma agonist pioglitazone to the MCD diet.


RESULTS
The MCD diet-induced steatohepatitis was accelerated in OLETF rats after 8 weeks. Steatosis preceded inflammation, which led to fibrosis and the development of steatohepatitis. The hepatic gene expression for transforming growth factor-beta, alpha1 procollagen and plasminogen activator inhibitor-1 was up-regulated in OLETF rats compared with LETO rats. The MCD + HF diet further enhanced insulin resistance and led to rapid development of pre-cirrhosis in OLETF rats by increasing the triglyceride pool, activating stellate cells, and up-regulating gene expression for sterol regulatory element-binding protein-1c and fatty acid synthase in the liver. In contrast, pioglitazone attenuated the MCD diet-induced steatohepatitis in OLETF rats but not in LETO rats by reversing the underlying pathogenesis involved in this model through improvement of insulin resistance. These results confirm a link between insulin resistance and the development/progression of steatohepatitis, at least partly via up-regulation of genes for lipogenesis, inflammation, and fibrogenesis, in animal models.


CONCLUSIONS
Insulin resistance and/or diabetes may accelerate the entire pathologic spectrum of NASH.
Ota
Tsuguhito
T
Department of Disease Control and Homeostasis, Kanazawa University Graduate School of Medical Science, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan.
Takamura
Toshinari
T
Kurita
Seiichiro
S
Matsuzawa
Naoto
N
Kita
Yuki
Y
Uno
Masafumi
M
Akahori
Hiroshi
H
Misu
Hirofumi
H
Sakurai
Masaru
M
Zen
Yoh
Y
Nakanuma
Yasuni
Y
Kaneko
Shuichi
S
D000821:Animal Feed; D000818:Animals; D002794:Choline / Q000494:pharmacology; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D004041:Dietary Fats / Q000494:pharmacology; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006946:Hyperinsulinism / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency / Q000494:pharmacology; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D047495:PPAR gamma / Q000819:agonists; D000077205:Pioglitazone; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020334:Rats, Inbred OLETF; D020318:Rats, Long-Evans; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D045162:Thiazolidinediones / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology
D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D045162:Thiazolidinediones; D016212:Transforming Growth Factor beta; D008715:Methionine; D002794:Choline; D000077205:Pioglitazone