IL-22 resolves MASLD via enterocyte STAT3 restoration of diet-perturbed intestinal homeostasis
The exponential rise in metabolic dysfunction-associated steatotic liver disease (MASLD) parallels the ever-increasing consumption of energy-dense diets, underscoring the need for effective MASLD-resolving drugs. MASLD pathogenesis is linked to obesity, diabetes, "gut-liver axis" alterations, and defective interleukin-22 (IL-22) signaling. Although barrier-protective IL-22 blunts diet-induced metabolic alterations, inhibits lipid intake, and reverses microbial dysbiosis, obesogenic diets rapidly suppress its production by small intestine-localized innate lymphocytes. This results in STAT3 inhibition in intestinal epithelial cells (IECs) and expansion of the absorptive enterocyte compartment. These MASLD-sustaining aberrations were reversed by administration of recombinant IL-22, which resolved hepatosteatosis, inflammation, fibrosis, and insulin resistance. Exogenous IL-22 exerted its therapeutic effects through its IEC receptor, rather than hepatocytes, activating STAT3 and inhibiting WNT-β-catenin signaling to shrink the absorptive enterocyte compartment. By reversing diet-reinforced macronutrient absorption, the main source of liver lipids, IL-22 signaling restoration represents a potentially effective interception of dietary obesity and MASLD.
Authors
- Bernd Schnabl (ORCID: https://orcid.org/0000-0002-6281-825X)
- Masafumi Ohira (ORCID: https://orcid.org/0000-0003-0775-3390)
- Haoqi Nina Zhao (ORCID: https://orcid.org/0000-0003-3908-630X)
- Gautam Bandyopadhyay (ORCID: https://orcid.org/0000-0003-4347-6036)
- Shabnam Shalapour (ORCID: https://orcid.org/0000-0002-4743-3706)
- Mojgan Hosseini (ORCID: https://orcid.org/0000-0002-6708-7126)
- Pejman Soroosh
- Peng Zhang (ORCID: https://orcid.org/0000-0003-0469-7151)
- Junlai Liu (ORCID: https://orcid.org/0000-0001-6460-9569)
- Santosh Lamichhane (ORCID: https://orcid.org/0000-0002-9292-3595)
- Allen Lee (ORCID: https://orcid.org/0000-0002-4861-7646)
- Kosuke Watari (ORCID: https://orcid.org/0000-0003-0260-2323)
- Michael Karin (ORCID: https://orcid.org/0000-0002-2758-6473)
- Hua Su (ORCID: https://orcid.org/0000-0003-2344-3886)
- Cristina Llorente (ORCID: https://orcid.org/0000-0001-8135-9186)
- Su-Ling Zeng (ORCID: https://orcid.org/0000-0002-2188-4285)
- Siddharth Mohan (ORCID: https://orcid.org/0009-0000-0134-0240)
- Pieter C. Dorrestein (ORCID: https://orcid.org/0000-0002-3003-1030)
- Jerrold M. Olefsky (ORCID: https://orcid.org/0000-0003-0392-1705)
- Li Gu
- Ju Youn Kim (ORCID: https://orcid.org/0009-0003-2452-4423)
- Nicholas Vo
- Mandy Zhu
- Irene Tsaur
- Vivian Duong
Institutions
- The University of Texas MD Anderson Cancer Center (US)
- Janssen (Belgium) (BE)
- University of San Diego (US)
- Turku Centre for Computer Science (FI)
- University of California San Diego (US)
- Janssen (United States) (US)
- University of Montana (US)
Publication Details
- Journal
- Cell Metabolism
- Published
- 2024-09-23
- DOI
- https://doi.org/10.1016/j.cmet.2024.08.012
- Citations
- 41
- Primary Topic
- Digestive system and related health
- Type
- article
- Field-Weighted Citation Impact
- 22.56
Funders
- National Institutes of Health
- University of California, San Diego
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke
- School of Medicine, University of California, San Diego