Non-alcoholic fatty liver disease (NAFLD) is a common problem with a wide variety of phenotypes. While its pathogenesis is still not fully understood, several risk factors for disease progression have been identified. Therefore, defining adequate animal models may serve to unreveal the pathogenesis in NAFLD. We studied Lewis and Sprague-Dawley rats of both genders (n ¼ 6) fed standard (Std) or high-fat (HF) diet for three weeks. Disease stage was assessed by haematoxylin -eosin, Azan Heidenheim and Oil-Red staining, apoptosis by single-stranded DNA (ssDNA) detection and liver regeneration by Ki-67 staining. Serum markers of liver injury and lipid metabolism including adipocytokines were analysed. Livers of both strains and genders fed with HF diet demonstrated evidence of steatosis. Lewis rats developed microvesicular steatosis whereas Sprague-Dawley rats presented macrovesicular steatosis accompanied by pronounced fibrosis. Female gender of both strains was associated with lower steatosis grade and higher proliferation rate (P , 0.05). Gender-specific differences were most prominent in Lewis rats on a HF diet, where females showed lower alkaline phosphatase, cholesterol, triglyceride and leptin levels and a more favourable low-density lipoprotein/high-density lipoprotein ratio than males (P , 0.05). Reverse transcriptase-polymerase chain reaction analysis was performed to demonstrate changes in expression of various genes important for liver regeneration, fibrosis and steatosis. HF diet induced downregulation of proangiogenic genes such as vascular endothelial growth factor receptor 1 and 2 (P , 0.05) in males was not present in females. In conclusion, strain and gender served major roles in disease progression. These differences should be considered when designing studies and may offer new ways to advance therapeutic strategies.Keywords: NAFLD, steatosis, rat strain, gender differences, high-fat diet Laboratory Animals 2013; 47: 43-52. DOI: 10.1177/0023677212473717The increasing burden of non-alcoholic fatty liver disease (NAFLD) has resulted in greater attention towards its associated rise in morbidity and mortality. Even children can be affected. Among the various risk factors identified so far, a high-fat (HF) diet is one major prerequisite.1 The spectrum of NAFLD ranges from bland fatty infiltration to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis and can eventually lead to end-stage liver disease with an increased risk of hepatocellular carcinoma.2 Our current understanding of the pathogenesis may be explained by the two-hit hypothesis, where steatosis induced by increased fatty acid synthesis and hepatic uptake is followed by oxidative stress and release of proinflammatory and profibrogenic mediators. Gender-specific differences in prevalence, degree of liver injury and adipocytokine levels of adolescents with NAFLD have been reported. 4 In general, NAFLD is more common in men than in women and a reversal in gender distribution following menopause suggests an oestrogen-mediated protec...

Rapid onset of fulminant hepatitis in asymptomatic LEC rats with elevated liver copper suggests that there is a critical threshold of liver copper which is important to trigger the course of WD.

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The outcome of consecutive hepatocyte transplants was explored in a rat model of Wilson's disease before the onset of fulminant hepatitis without preconditioning regimens. Rats received a high-copper diet in order to induce a rapid induction of liver failure. Sham-operated rats (15/15) developed jaundice and fulminant hepatitis, and they died within 4 weeks of first transplantation. Despite the continuation of a high dietary copper challenge, long-term survival was observed for a notable proportion of the transplanted animals (7/18). All survivors displayed normalized levels of hepatitis-associated serum markers and ceruloplasmin oxidase activity by posttransplant days 50 and 98, respectively. The liver copper concentrations, the liver histology, and the expression of marker genes were significantly restored within 4 months of transplantation in comparison with the control group. The high expression of a copper transporter gene (ATPase Cu þþ transporting beta polypeptide) in the livers of the survivors indicated a high rate of repopulation by donor hepatocytes. Our data suggest that repeated cell transplantation can overcome the limitations of a single therapy session in rats with severe hepatic disease by functionally restoring the host liver without preconditioning.

Losartan increased hepatic blood flow, reduced HSC activation and liver fibrosis, but interfered with hepatocyte proliferation after partial hepatectomy in cirrhotic livers.