Development of Non-alcoholic Steatohepatitis and Nodular Regenerative Hyperplasia in C57BL/6J Mice Fed a Fructose-containing Western Diet.

Abstract

We generated a novel disease mouse model in which a fructose-containing western diet (FD) induces development of non-alcoholic steatohepatitis (NASH). C57BL/6J mice were fed FD for 60 weeks and body weight and blood pressure were monitored. Plasma cholesterol level was measured at the end of the experiments. Histopathology of NASH was examined by hematoxylin and eosin staining, Masson-Trichrome staining, periodic acid-Schiff staining, and immunohistochemistry against a proliferation marker. Circadian gene expression levels were compared by sampling the livers in 4-h intervals, followed by quantitative RT-PCR analysis. FD-fed mice developed obesity, transient hypertension, hypercholesterolemia, and liver adiposity. The mice spontaneously developed hepatic nodules, which were diagnosed as non-neoplastic nodular regenerative hyperplasia. FD-fed mice had increased expression of growth factor genes and cirrhosis markers compared to control mice. Circadian expression of lipid metabolism genes was deregulated by FD intake. C57BL/6J mice fed FD developed non-alcoholic steatohepatitis and nodular regenerative hyperplasia over time.