Basic Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Sep 7, 2020; 26(33): 4933-4944
Published online Sep 7, 2020. doi: 10.3748/wjg.v26.i33.4933
Tumor necrosis factor alpha receptor 1 deficiency in hepatocytes does not protect from non-alcoholic steatohepatitis, but attenuates insulin resistance in mice
Sena Bluemel, Yanhan Wang, Suhan Lee, Bernd Schnabl
Sena Bluemel, Yanhan Wang, Suhan Lee, Bernd Schnabl, Department of Medicine, University of California San Diego, La Jolla, CA 92093, United States
Sena Bluemel, Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich 8091, Switzerland
Yanhan Wang, Bernd Schnabl, Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161, United States
Author contributions: Bluemel S performed experiments and wrote the manuscript; Wang Y and Lee S assisted with experiments; Schnabl B supervised the study and edited the manuscript; All authors approved the final version of the manuscript.
Supported by the Swiss National Science Foundation, No. P2SKP3_158649, No. P3400PB_171581, and No. P3P3PB_171582 (to Bluemel S); NIH grants (in part), No. R01 AA24726, No. U01 AA026939, and services provided by P30 DK120515 (to Schnabl B).
Institutional animal care and use committee statement: All animal studies were reviewed and approved by the Institutional Animal Care and Use Committee of the University of California, San Diego (IACUC Protocol No. S09042).
Conflict-of-interest statement: Schnabl B has been consulting for Ferring Research Institute, HOST Therabiomics, Intercept Pharmaceuticals and Patara Pharmaceuticals. Schnabl B’s institution UC San Diego has received research support from Axial Biotherapeutics, BiomX, CymaBay Therapeutics, NGM Biopharmaceuticals, and Synlogic Operating Company.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Bernd Schnabl, MD, Professor, Department of Medicine, University of California San Diego, Biomedical Research Facility 2 (BRF2), Room 4A22, 9500 Gilman Drive, MC0063, La Jolla, CA 92093, United States. beschnabl@ucsd.edu
Received: March 28, 2020
Peer-review started: March 28, 2020
First decision: May 21, 2020
Revised: July 21, 2020
Accepted: August 12, 2020
Article in press: August 12, 2020
Published online: September 7, 2020
Processing time: 159 Days and 18.8 Hours
ARTICLE HIGHLIGHTS
Research background

Understanding the pathogenesis of non-alcoholic steatohepatitis (NASH) is crucial for the development of new therapies. The inflammatory cytokine tumor necrosis factor alpha (TNF-α) is important for the progression of liver disease. It binds to two receptors, TNF receptor 1 (TNFR1) and TNFR2.

Research motivation

TNF signaling via TNFR1 has been hypothesized to be important for the development of NASH and hepatocellular carcinoma in whole-body knockout animal models.

Research objectives

The aim of our study was to investigate the hepatocyte specific role of TNFR1 signaling for diet-induced steatohepatitis.

Research methods

NASH was induced by a 20-wk western-style fast-food diet in mice deficient of TNFR1 in hepatocytes (TNFR1ΔHEP) and their wild-type littermates (TNFR1fl/fl). Features of NASH as well as glucose tolerance and insulin resistance were assessed.

Research results

Obesity, liver injury, inflammation, steatosis, and fibrosis was not different between TNFR1ΔHEP and TNFR1fl/fl mice. However, Tnfr1 deficiency in hepatocytes protected mice against glucose intolerance and insulin resistance.

Research conclusions

Our results do not indicate that inhibition of TNFR1 signaling in hepatocytes can protect from diet-induced NASH. However, improved insulin resistance in this model confirms the important role of the liver for glucose homeostasis during obesity.

Research perspectives

Compensatory mechanisms, possibly occurring via TNFR2 signaling, need to be investigated in future studies.