Nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH) is highly prevalent in modern societies frequently consuming diets rich in fats and carbohydrates. NASH is characterized by liver steatosis, inflammation and increased risk for liver fibrosis in human. There is no single animal model available that encompasses the defining features of NASH; therefore, it is of importance to thoroughly characterize available rodent models for NASH research and new drug discovery. Foz/foz mice have a mutation in the Alms1 gene, a ubiquitous protein essential for proper primary cilium function. They have similar defects such as metabolic syndrome, NASH and liver fibrosis to human with the same gene mutation. To better characterize the model, foz/foz mice were fed with western diet (WD, D12079B) for various duration. Compared with WT mice, foz/foz mice on WD had (1) increased BW gain driven by hyperphagia; (2) insulin/leptin resistance with decreased adiponectin levels and hyperlipidemia; (3) increased fat mass and hepatomegaly; (4) increased liver enzymes and elevated TIMP1 in plasma; (5) Liver gene expressions profiles of foz/foz mice showed up-regulation of fibrogenic genes and Lipogenesis, inflammation genes. Histopathology assessment showed foz/foz mice developed severe hepatic steatosis and increased marker of macrophage populations (F4/80 IHC staining). liver collagen content was significantly increased at 16 and 24 wks post WD feeding (PSR staining) compared to wild type mice fed the same diet. Our results suggest that the foz/foz mouse model has robust hallmark features of NASH such as metabolic syndrome, steatohepatitis, and fibrosis. In addition, our data suggest the presence of metabolic complications in other organs as well, as foz/foz mice develop proteinuria over time. The WD-induced foz/foz model exhibits several clinically relevant features and serves as a translational model of NASH.
J. Liu: None. S. Wang: None. K.E. D’Aquino: Employee; Self; Janssen Pharmaceuticals, Inc. Employee; Spouse/Partner; Janssen Pharmaceuticals, Inc. N.H. Wallace: None. M.M. Rankin: Employee; Self; Janssen Pharmaceuticals, Inc. Stock/Shareholder; Self; Johnson & Johnson. F. Du: None. S.A. Hinke: Employee; Self; Janssen Pharmaceuticals, Inc. Stock/Shareholder; Self; Johnson & Johnson. K.A. Albarazanji: None. A.R. Nawrocki: Employee; Self; Janssen Pharmaceuticals, Inc.