Article

Diabetologia

, Volume 55, Issue 12, pp 3382-3391

Protection from non-alcoholic steatohepatitis and liver tumourigenesis in high fat-fed insulin receptor substrate-1-knockout mice despite insulin resistance

  • A. NakamuraAffiliated withDepartment of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University
  • , K. TajimaAffiliated withDepartment of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University
  • , K. ZolzayaAffiliated withDepartment of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University
  • , K. SatoAffiliated withDepartment of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University
  • , R. InoueAffiliated withDepartment of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University
  • , M. YonedaAffiliated withDivision of Gastroenterology, Graduate School of Medicine, Yokohama City University
  • , K. FujitaAffiliated withDivision of Gastroenterology, Graduate School of Medicine, Yokohama City University
  • , Y. NozakiAffiliated withDivision of Gastroenterology, Graduate School of Medicine, Yokohama City University
  • , K. C. KubotaAffiliated withDepartment of Surgical Pathology, Hokkaido University Hospital
    • , H. HagaAffiliated withDepartment of Surgical Pathology, Hokkaido University Hospital
    • , N. KubotaAffiliated withDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo
    • , Y. NagashimaAffiliated withDepartment of Molecular Pathology, Graduate School of Medicine, Yokohama City University
    • , A. NakajimaAffiliated withDivision of Gastroenterology, Graduate School of Medicine, Yokohama City University
    • , S. MaedaAffiliated withDivision of Gastroenterology, Graduate School of Medicine, Yokohama City University
    • , T. KadowakiAffiliated withDepartment of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo
    • , Y. TerauchiAffiliated withDepartment of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University Email author 

Abstract

Aims/hypothesis

Epidemiological studies have revealed that obesity and diabetes mellitus are independent risk factors for the development of non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma. However, the debate continues on whether insulin resistance as such is directly associated with NASH and liver tumourigenesis. Here, we investigated the incidence of NASH and liver tumourigenesis in Irs1 −/− mice subjected to a long-term high-fat (HF) diet. Our hypothesis was that hepatic steatosis, rather than insulin resistance may be related to the pathophysiology of these conditions.

Methods

Mice (8 weeks old, C57Bl/6J) were given free access to standard chow (SC) or an HF diet. The development of NASH and liver tumourigenesis was evaluated after mice had been on the above-mentioned diets for 60 weeks. Similarly, Irs1 −/− mice were also subjected to an HF diet for 60 weeks.

Results

Long-term HF diet loading, which causes obesity and insulin resistance, was sufficient to induce NASH and liver tumourigenesis in the C57Bl/6J mice. Obesity and insulin resistance were reduced by switching mice from the HF diet to SC, which also protected these mice against the development of NASH and liver tumourigenesis. However, compared with wild-type mice fed the HF diet, Irs1 −/− mice fed the HF diet were dramatically protected against NASH and liver tumourigenesis despite the presence of severe insulin resistance and marked postprandial hyperglycaemia.

Conclusions/interpretation

IRS-1 inhibition might protect against HF diet-induced NASH and liver tumourigenesis, despite the presence of insulin resistance.

Keywords

High-fat diet Insulin receptor substrate-1 Insulin resistance Liver tumourigenesis Non-alcoholic steatohepatitis