Nonalcoholic Steatohepatitis and HCC in a Hyperphagic Mouse Accelerated by Western Diet

Souradipta Ganguly, German Aleman Muench, Linshan Shang, Sara Brin Rosenthal, Gibraan Rahman, Ruoyu Wang, Yanhan Wang, Hyeok Choon Kwon, Anthony M. Diomino, Tatiana Kisseleva, Pejman Soorosh, Mojgan Hosseini, Rob Knight, Bernd Schnabl, David A. Brenner, Debanjan Dhar

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Background & Aims: How benign liver steatosis progresses to nonalcoholic 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 a Western diet (WD), we aimed to elucidate the cross-talk and kinetics of hepatic and extrahepatic alterations during NASH–HCC progression, as well as regression. Methods: Hyperphagic mice lacking a functional Alms1 gene (Foz/Foz) and wild-type littermates were fed WD or standard chow for 12 weeks for NASH/fibrosis and for 24 weeks for HCC development. NASH regression was modeled by switching back to normal chow after NASH development. Results: Foz+WD mice were steatotic within 1 to 2 weeks, developed NASH by 4 weeks, and grade 3 fibrosis by 12 weeks, accompanied by chronic kidney injury. Foz+WD mice that continued on WD progressed to cirrhosis and HCC within 24 weeks and had reduced survival as a result of cardiac dysfunction. However, NASH mice that were switched to normal chow showed NASH regression, improved survival, and did not develop HCC. Transcriptomic and histologic analyses of Foz/Foz NASH liver showed strong concordance with human NASH. NASH was preceded by an early disruption of gut barrier, microbial dysbiosis, lipopolysaccharide 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. Conclusions: The 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.

Original languageEnglish (US)
Pages (from-to)891-920
Number of pages30
JournalCellular and Molecular Gastroenterology and Hepatology
Volume12
Issue number3
DOIs
StatePublished - Jan 1 2021
Externally publishedYes

Bibliographical note

Funding Information:
Funding Supported by the American Liver Foundation (ALF) Liver Scholar award, UC San Diego Altman Clinical and Translational Research Institute (ACTRI)/ National Institutes of Health grant KL2TR001444 , The San Diego Digestive Diseases Research Center (SDDRC) ( National Institutes of Health grant DK120515 ), and the Southern California Research Center for Alcoholic Liver and Pancreatic Diseases (ALPD) and Cirrhosis funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA)/ National Institutes of Health grant 5P50AA011999 (D.D.); by National Institutes of Health grants U01AA022614 , P50AA011999 , and AI043477 , and an unrestricted research grant from Janssen (D.A.B.); and by National Institutes of Health grants R01DK101737 , U01AA022614 , R01DK099205 , and R01DK111866 (T.K.).

Funding Information:
Conflicts of interest The authors disclose no conflicts. The University of California San Diego and D.A.B receives grant support from Janssen.

Funding Information:
Funding Supported by the American Liver Foundation (ALF) Liver Scholar award, UC San Diego Altman Clinical and Translational Research Institute (ACTRI)/National Institutes of Health grant KL2TR001444, The San Diego Digestive Diseases Research Center (SDDRC) (National Institutes of Health grant DK120515), and the Southern California Research Center for Alcoholic Liver and Pancreatic Diseases (ALPD) and Cirrhosis funded by the National Institute on Alcohol Abuse and Alcoholism (NIAAA)/National Institutes of Health grant 5P50AA011999 (D.D.); by National Institutes of Health grants U01AA022614, P50AA011999, and AI043477, and an unrestricted research grant from Janssen (D.A.B.); and by National Institutes of Health grants R01DK101737, U01AA022614, R01DK099205, and R01DK111866 (T.K.).The authors thank Kevin Lam, Naser Khader, Asra Irfan, and Rolando Arreola for their help with experiments, and the University of California San Diego Microscopy Core (NS047101) for Nanozoomer imaging support. Souradipta Ganguly, PhD (Conceptualization: Equal; Data curation: Lead; Formal analysis: Lead; Investigation: Equal; Methodology: Equal; Writing ? original draft: Equal), German Aleman Muench, PhD (Data curation: Supporting; Formal analysis: Supporting; Investigation: Supporting; Validation: Supporting; Writing ? original draft: Supporting), Linshan Shang, PhD (Data curation: Supporting; Formal analysis: Supporting; Methodology: Supporting; Validation: Supporting), Sara Brin Rosenthal, PhD (Data curation: Supporting; Formal analysis: Supporting; Software: Supporting; Visualization: Supporting), Gibraan Rahman, BS (Data curation: Supporting; Formal analysis: Supporting; Software: Supporting; Visualization: Supporting), Ruoyu Wang, BS (Formal analysis: Supporting; Methodology: Supporting), Yanhan Wang, PhD (Investigation: Supporting; Methodology: Supporting; Validation: Supporting), Hyeok Choon Kwon, MD, PhD (Investigation: Supporting; Methodology: Supporting), Anthony M Diomino, BS (Formal analysis: Supporting; Methodology: Supporting; Software: Supporting), Tatiana Kisseleva, MD, PhD (Investigation: Supporting; Methodology: Supporting; Resources: Supporting), Pejman Soorosh, PhD (Formal analysis: Supporting; Investigation: Supporting; Methodology: Supporting; Resources: Supporting), Mojgan Hosseini, MD (Formal analysis: Supporting; Methodology: Supporting), Rob Knight, PhD (Formal analysis: Supporting; Investigation: Supporting; Methodology: Supporting; Software: Supporting), Bernd Schnabl, MD (Formal analysis: Supporting; Investigation: Supporting; Methodology: Supporting), David A Brenner, MD (Conceptualization: Equal; Funding acquisition: Equal; Resources: Equal; Supervision: Equal), Debanjan Dhar, PhD (Conceptualization: Lead; Data curation: Equal; Formal analysis: Equal; Funding acquisition: Equal; Investigation: Equal; Methodology: Equal; Project administration: Lead; Resources: Equal; Supervision: Lead; Writing ? original draft: Lead) Conflicts of interest The authors disclose no conflicts. The University of California San Diego and D.A.B receives grant support from Janssen.

Publisher Copyright:
© 2021 The Authors

Keywords

  • Gut Inflammation
  • Hepatocellular Carcinoma
  • Liver Inflammation
  • NASH Regression
  • Nonalcoholic Steatohepatitis

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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