Novel effect of ezetimibe to inhibit the development of non-alcoholic fatty liver disease in Fatty Liver Shionogi mouse.

AIM: Several studies using experimental non-alcoholic fatty liver disease (NAFLD) models have shown that ezetimibe, an inhibitor of cholesterol absorption mainly in the intestine, not only protects against diet-induced hyperlipidemia, but also attenuates liver steatosis. The aim of this study was to clarify whether ezetimibe inhibits the development of NAFLD and to elaborate the mechanism of ezetimibe to inhibit the development of NAFLD using Fatty Liver Shionogi (FLS) mice, a spontaneous model of NAFLD/non-alcoholic steatohepatitis. METHODS: Male FLS mice at 20 weeks of age were divided into two groups (n = 7 in each group). Mice fed a normal laboratory chow, CRF-1 or CRF-1 containing 0.005% w/w ezetimibe (7 mg/kg per day) for 4 weeks. After 4-week treatment with ezetimibe, the livers of each group of mice were subjected to histological as well as molecular evaluation. RESULTS: Ezetimibe administration for 4 weeks was associated with improvement of steatosis and fibrosis of the liver in normal diet-fed FLS mice. Ezetimibe reduced hepatic reactive oxygen species generation and prevented ubiquitination and protein degradation of microsomal triglyceride transfer protein (MTP), a key molecule for very low-density lipoprotein assembly and export, via downregulation of the protein expression of Skp2 and CDC20. CONCLUSION: Ezetimibe not only reduced lipid synthesis in the liver, but also promoted lipid discharge from the liver by preventing post-translational degradation of MTP via a reduction of hepatic reactive oxygen species generation, leading to inhibition of the development of NAFLD.

Involvement of microsomal triglyceride transfer protein in nonalcoholic steatohepatitis in novel spontaneous mouse model.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is currently recognized as a global health issue and encompasses a wide spectrum of entities, ranging from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH). The lack of a spontaneous animal model of NASH, however, has hampered basic research in this field. METHODS: We examined the hepatic lesions in the inbred Fatty Liver Shionogi (FLS) mouse, which exhibits type 2 diabetes, and investigated the molecular mechanism leading to NAFLD/NASH. Using vector-mediated hepatic expression of microsomal triglyceride transfer protein (MTP), a key molecule for very low density lipoprotein (VLDL) assembly and export, its contribution to the hepatic lesions as well as to glucose intolerance was examined. RESULTS: The FLS mouse, maintained on normal chow, exhibited excessive hepatic triglyceride (TG) accumulation due to impaired VLDL secretion, and subsequently hepatic lesions comparable to NASH, with increased expression of inflammatory molecules as well as insulin resistance. Gene expression and Western blot analyses demonstrated reduced hepatic expression of MTP in the FLS mouse. Hepatic induction of MTP resulted in a reduction in hepatic TG accumulation, improvement of VLDL export, and amelioration of NASH-like lesions, as well as glucose intolerance. CONCLUSIONS: These data suggest that the FLS mouse could serve as a spontaneous model of NASH with insulin resistance, and that reduced MTP is involved in the development of NASH, pointing towards MTP as a critical target for the prevention and treatment of NASH.

A novel mouse model for type 2 diabetes and non-alcoholic fatty liver disease: spontaneous amelioration of diabetes by augmented beta cell mass.

Given the potential for beta-cells to increase their mass, glucose intolerance might be ameliorated by a compensatory increase in beta-cell mass. However, it remains uncertain whether such amelioration is feasible in vivo. In this study, we investigated glucose tolerance, islet morphology, and islet gene expression of Fatty Liver Shionogi (FLS) mice, a model for non-alcoholic fatty liver disease (NAFLD). Relative to control mice, FLS mice showed an age-dependent increase in glucose intolerance up to the age of 24 weeks, leading to the development of diabetes. After this time, glucose tolerance ameliorated spontaneously and diabetes resolved by 48 week of age, associated with marked hyperinsulinemia. Islets of the FLS mice demonstrated a marked increase in beta-cell mass with an increase in beta-cell numbers. Islet gene expression analysis in FLS mice demonstrated no changes in gene expression of glucokinase or insulin receptor substrate 2. These data demonstrated that the 24-week-old FLS mouse is a model for type 2 diabetes with NAFLD and that the 48-week-old FLS mouse exhibits spontaneous amelioration of type 2 diabetes associated with augmented beta-cell number/mass.

Present state of diabetes management in the elderly, Japan.

A recent dramatic increase in elderly patients with diabetes mellitus has made the proper management of the disease in this population more important. Here, we discuss the present status of diabetes management in the elderly in Japan. As a characteristic feature of elderly persons, body weight reduction is difficult, because of the profound adaptive reduction in resting energy expenditure under calorie restriction in the elderly. However, hyperglycemia increases the risk for diabetic complications, except proliferative retinopathy, similarly in elderly and non-elderly. Of note, there is marked clinical heterogeneity in this generation in the following aspects: duration, complication status (past aspect), insulin secretion, insulin sensitivity, familial support and physical exercise/activity (present aspect), as well as the expected lifespan (future aspect). This heterogeneity among the elderly should render diabetes treatment diverse, and in fact, one of the largest surveys in Japan demonstrated significant diversity in diabetes management in the elderly. In Japan, thus, the present management of diabetes in the elderly is considerably diverse, reflecting the clinical heterogeneity among elderly patients with diabetes. Further clinical evidence is awaited for the establishment of proper and safe management of diabetes in the elderly.