IL-22 Resolves MASLD via Enterocyte STAT3 Restoration of Diet-Perturbed Intestinal Homeostasis

Authors

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

Publication Date

10-1-2024

Journal

Cell Metabolism

DOI

10.1016/j.cmet.2024.08.012

PMID

39317186

PMCID

PMC11631175

PubMedCentral® Posted Date

10-1-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Animals, Humans, Male, Mice, Diet, Diet, High-Fat, Enterocytes, Fatty Liver, Homeostasis, Interleukin-22, Interleukins, Intestinal Mucosa, Intestines, Mice, Inbred C57BL, STAT3 Transcription Factor, IL-22, MASLD, STAT3, WNT-β-catenin, hepatosteatosis, lipid absorption

Published Open-Access

yes

Recommended Citation

Zhang, Peng; Liu, Junlai; Lee, Allen; et al., "IL-22 Resolves MASLD via Enterocyte STAT3 Restoration of Diet-Perturbed Intestinal Homeostasis" (2024). Faculty, Staff and Student Publications. 3068.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/3068