Hepatic interleukin-1 receptor type 1 signalling regulates insulin sensitivity in the early phases of nonalcoholic fatty liver disease
Nadine Gehrke
I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55131 Germany
Search for more papers by this authorLea J. Hofmann
I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55131 Germany
Search for more papers by this authorBeate K. Straub
Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Search for more papers by this authorFrank Rühle
Bioinformatics Core Facility, Institute of Molecular Biology (IMB), Mainz, Germany
Search for more papers by this authorAri Waisman
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Search for more papers by this authorPeter R. Galle
I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55131 Germany
Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Search for more papers by this authorCorresponding Author
Jörn M. Schattenberg
I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55131 Germany
Correspondence
Jörn M. Schattenberg, Metabolic Liver Research Program, I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.
Email: [email protected]
Search for more papers by this authorNadine Gehrke
I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55131 Germany
Search for more papers by this authorLea J. Hofmann
I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55131 Germany
Search for more papers by this authorBeate K. Straub
Institute of Pathology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Search for more papers by this authorFrank Rühle
Bioinformatics Core Facility, Institute of Molecular Biology (IMB), Mainz, Germany
Search for more papers by this authorAri Waisman
Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Search for more papers by this authorPeter R. Galle
I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55131 Germany
Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Search for more papers by this authorCorresponding Author
Jörn M. Schattenberg
I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, 55131 Germany
Correspondence
Jörn M. Schattenberg, Metabolic Liver Research Program, I. Department of Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.
Email: [email protected]
Search for more papers by this authorAbstract
Background
Nonalcoholic fatty liver disease (NAFLD) is associated with hepatic as well as systemic insulin resistance even in the absence of type 2 diabetes. The extent and pathways through which hepatic inflammation modulates insulin sensitivity in NAFLD are only partially understood. We explored the contribution of hepatic interleukin (IL)-1 signalling in a novel conditional knockout mouse model and expand the knowledge on this signalling pathway with regard to its liver-specific functions.
Methods
A high-fat, high-carbohydrate diet (HFD) over 12 weeks was used in male hepatocyte-specific IL-1 receptor type 1 (IL-1R1) knockout mice (Il1r1Hep−/–) and wild-type (WT) littermates.
Results
Both genotypes developed an obese phenotype and accompanying macrovesicular hepatic steatosis. In contrast to WT mice, microvesicular steatosis and ballooning injury was less pronounced in HFD-fed Il1r1Hep−/– mice, and alanine aminotransferase remained in the normal range. This was paralleled by the suppression of injurious and proinflammatory hepatic c-Jun N-terminal kinases and extracellular signal-regulated kinases signalling, stable peroxisome proliferator activated receptor gamma coactivator-1alpha and farnesoid X receptor-alpha expression and preservation of mitochondrial function. Strikingly, despite HFD-feeding Il1r1Hep−/– mice remained highly insulin sensitive as indicated by lower insulin levels, homeostatic model assessment for insulin resistance, higher glucose tolerance, more stable hepatic insulin signalling cascade, and less adipose tissue inflammation compared to the WT.
Conclusions
The current data highlights that hepatocyte IL-1R1 contributes to hepatic and extrahepatic insulin resistance. Future liver-directed therapies in NAFLD could have effects on insulin sensitivity when improving hepatic inflammation and IL-1R1 signalling.
CONFLICT OF INTEREST
JMS declares consultant honorary from BMS, Boehringer Ingelheim, Echosens, Genfit, Gilead Sciences, Intercept Pharmaceuticals, Madrigal, Merck, Nordic Bioscience, Novartis, Pfizer, Roche, Sanofi, and Siemens Healthcare GmbH, research funding from Gilead Sciences, Boehringer Ingelheim, Siemens Healthcare GmbH, and speaker honorarium form Falk Foundation. The other authors declare no conflict of interest.
Open Research
DATA AVAILABILITY STATEMENT
Data available on request from the authors.
Supporting Information
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Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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