Insulin resistance accelerates a dietary rat model of nonalcoholic steatohepatitis

  • Ota T
  • Takamura T
  • Kurita S
 et al. 
  • 6

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Abstract

BACKGROUND & AIMS: 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.

Author-supplied keywords

  • Animal Feed
  • Animals
  • Choline/pharmacology
  • Collagen Type I/genetics
  • Diabetes Mellitus, Type 2/drug therapy/metabolism/
  • Dietary Fats/pharmacology
  • Disease Models, Animal
  • Fatty Liver/metabolism/pathology/*physiopathology
  • Hyperinsulinism/drug therapy/metabolism/*physiopat
  • Hypoglycemic Agents/pharmacology
  • Insulin Resistance/*physiology
  • Liver/drug effects/pathology
  • Male
  • Methionine/deficiency/pharmacology
  • Obesity/drug therapy/metabolism/*physiopathology
  • PPAR gamma/agonists
  • Plasminogen Activator Inhibitor 1/genetics
  • RNA, Messenger/metabolism
  • Rats
  • Rats, Inbred OLETF
  • Rats, Long-Evans
  • Sterol Regulatory Element Binding Protein 1/geneti
  • Thiazolidinediones/pharmacology
  • Transforming Growth Factor beta/genetics
  • Up-Regulation/physiology

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Authors

  • T Ota

  • T Takamura

  • S Kurita

  • N Matsuzawa

  • Y Kita

  • M Uno

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