How benign liver steatosis progresses to non-alcoholic steatohepatitis (NASH), fibrosis and hepatocellular carcinoma (HCC) remains elusive. NASH progression entails diverse pathogenic mechanisms and relies on complex cross-talk between multiple tissues such as the gut, adipose tissues, liver and the brain. Using a hyperphagic mouse fed with Western diet (WD), we aimed to elucidate the cross-talk and kinetics of hepatic and extra-hepatic alterations during NASH-HCC progression as well as regression.
Hyperphagic mice lacking a functional Alms1 gene (Foz/Foz), and WT littermates were fed WD or standard chow for 12w for NASH/fibrosis and 24w for HCC development. NASH regression was modeled by switching back to normal chow after NASH development.
Foz+WD mice were steatotic within 1-2w, developed NASH by 4w, and grade 3 fibrosis by 12w, accompanied by chronic kidney injury. Foz+WD mice that continued on WD progressed to cirrhosis and HCC within 24w and had reduced survival due to cardiac dysfunction. However, NASH mice that were switched to normal chow showed NASH regression, improved survival and did not develop HCC. Transcriptomic and histological analyses of Foz/Foz NASH liver showed strong concordance with human NASH. NASH was preceded by an early disruption of gut barrier, microbial dysbiosis, LPS leakage and intestinal inflammation. This led to acute phase liver inflammation in Foz+WD mice, characterized by neutrophil infiltration and increased levels of several chemokines/cytokines. The liver cytokine/chemokine profile evolved as NASH progressed with subsequent predominance by monocyte recruitment.
Foz+WD model closely mimics the pathobiology and gene signature of human NASH with fibrosis and subsequent HCC. Foz+WD mice provide a robust and relevant preclinical model of NASH, NASH associated HCC, chronic kidney injury, and heart failure.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Author