IL-22 resolves MASLD via enterocyte STAT3 restoration of diet-perturbed intestinal homeostasis - UTU Research Portal

A1 Refereed original research article in a scientific journal

IL-22 resolves MASLD via enterocyte STAT3 restoration of diet-perturbed intestinal homeostasis

Authors: Zhang, Peng; Liu, Junlai; Lee, Allen; Tsaur, Irene; Ohira, Masafumi; Duong, Vivian; Vo, Nicholas; Watari, Kosuke; Su, Hua; Kim, Ju Youn; Gu, Li; Zhu, Mandy; Shalapour, Shabnam; Hosseini, Mojgan; Bandyopadhyay, Gautam; Zeng, Suling; Llorente, Cristina; Zhao, Haoqi Nina; Lamichhane, Santosh; Mohan, Siddharth; Dorrestein, Pieter C.; Olefsky, Jerrold M.; Schnabl, Bernd; Soroosh, Pejman; Karin, Michael

Publication year: 2024

Journal: Cell Metabolism

Journal name in source: Cell metabolism

Volume: 36

Issue: 10

First page : 2341

Last page: 2354

ISSN: 1550-4131

eISSN: 1932-7420

DOI: https://doi.org/10.1016/j.cmet.2024.08.012

Publication's open availability at the time of reporting: Open Access

Publication channel's open availability : Partially Open Access publication channel

Web address : https://doi.org/10.1016/j.cmet.2024.08.012

Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/458532888

Self-archived copy's licence: CC BY

Self-archived copy's version: Publisher`s PDF

Abstract

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.

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Funding information in the publication:
Research was supported by grants from the NIH (R37AI043477 and R01DK133448 to M.K.; DK120515 to the SDDRC), Janssen Research & Development, the National Cancer Institute Cancer Center Support Grant (CCSG) (P30CA23100 to TTSR), and the UCSD School of Medicine Microscopy Core (NINDS P30-NS047101). This publication includes data generated at the UCSD IGM Genomics Center utilizing an Illumina NovaSeq 6000 that was purchased with funding from a National Institutes of Health SIG grant (#S10 OD026929).