Pathophysiological Features of Rat Models of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis.

Nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is caused by various factors, including genetic and/or environmental factors, and has complicated pathophysiological features during the development of the disease. NAFLD/NASH is recognized as an unmet medical need, and NAFLD/NASH animal models are essential tools for developing new therapies, including potential drugs and biomarkers. In this review, we describe the pathological features of the NAFLD/NASH rat models, focusing on the histopathology of hepatic fibrosis. NAFLD/NASH rat models are divided into three categories: diet-induced, genetic, and combined models based on diet, chemicals, and genetics. Rat models of NASH with hepatic fibrosis are especially expected to contribute to the development of new therapies, such as drugs and biomarkers.

Choline-deficient Diet-induced NAFLD Animal Model Recaptures Core Human Pathophysiology With Similar Gene Co-expression Networks.

BACKGROUND/AIM: Nonalcoholic fatty liver disease (NAFLD) is a wide spectrum of liver disorders ranging from simple steatosis to nonalcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma. Recently, the prevalence of NAFLD has dramatically increased, and treatment is urgently needed. Animal models are often used to understand the molecular mechanisms of disease development and progression, but their relevance to human diseases has not been fully understood. This study aimed to establish the usefulness of the animal model for preclinical research, we evaluated its relevance to human disease by gene expression analysis. MATERIALS AND METHODS: We performed weighted gene co-expression network analysis of liver tissues from a choline-deficient L-amino acid-defined (CDAA) diet-induced NAFLD animal model. In addition, module preservation analysis was conducted to evaluate similarity across species. RESULTS: Several modules were identified to be associated with disease severity, and their gene co-expression network was found to be preserved in the human NAFLD datasets. Of note, module brown (immune cell clusters involved in inflammatory responses) was positively associated with disease severity, and its gene co-expression network was highly preserved in the human datasets. Tyrobp, Laptm5 and Lgals3 were identified as hub genes in the brown module, and their increased expression was confirmed in the human datasets. CONCLUSION: CDAA diet-induced NAFLD animal model recaptured key aspects of human pathophysiology (especially immune cell functions) and is thought to be a powerful tool for understanding the molecular mechanisms of NAFLD development and progression.

Establishment of a new nonalcoholic steatohepatitis model; Ovariectomy exacerbates nonalcoholic steatohepatitis-like pathology in diabetic rats.

An increasing number of patients worldwide are being diagnosed with nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NAFLD/NASH) because of the growing prevalence of obesity and metabolic disorders. The incidence of NAFLD is higher in postmenopausal women than in premenopausal women. The decline in the level of female hormones might have an effect on the deterioration of metabolism. In the present study, we investigated the potential of Spontaneously Diabetic Torii (SDT) fatty rats as a new animal model for NAFLD. We created a menopausal model by ovariectomy (OVX) in female rats. Sprague-Dawley (SD) rats, SDT rats, and SDT-fatty rats were divided into sham and OVX groups and maintained until 40 weeks of age. The results showed that OVX-induced weight gain was observed in SD and SDT rats. In addition, OVX-induced hepatic triglyceride accumulation was increased in all strains, and there was a significant increase in hepatic triglyceride levels in OVX-SDT fatty rats compared to those in Sham-SD rats. Furthermore, liver fibrosis was worsened in the OVX-SDT fatty rats. In addition, OVX-induced increase in blood ALT level was observed in SDT-fatty rats. Gene expression analysis showed OVX-induced upregulation of Srebp1 expression and downregulation of Pemt and Mttp in OVX rats. These results indicate that OVX-SDT fatty rats exhibit NASH with more severe hepatic fibrosis than untreated animals, suggesting that OVX-induced estrogen reduction may have enhanced lipid synthesis in the liver. It is also possible, although hypothetical, that OVX may decrease VLDL secretion, which may more strongly induce NASH.

ALKBH8 promotes bladder cancer growth and progression through regulating the expression of survivin.

Human AlkB homolog 8 (ALKBH8) is highly expressed in high-grade, superficially and deeply invasive bladder cancer. Moreover, ALKBH8 knockdown induces apoptosis in bladder cancer cells. However, the underlying anti-apoptotic mechanism of ALKBH8 in bladder cancer cells has thus far remained unclear. Moreover, there is no direct evidence that highly expressed ALKBH8 is involved in tumor progression in vivo. We here show that ALKBH8 knockdown induced apoptosis via downregulating the protein expression of survivin, an anti-apoptotic factor also exhibiting increased levels in bladder cancer. We also clarify that ALKBH8 transgenic mice showed an accelerated rate of bladder tumor mass and invasiveness in an N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced bladder cancer model. These findings suggest that the high expression of ALKBH8 is critical for the growth and progression of bladder cancer.