作者
Peng Zhang,Junlai Liu,Allen Lee,Igor Tsaur,Masafumi Ohira,Vanessa Duong,Nguyen T. K. Vo,Kosuke Watari,Hua Su,Ju Youn Kim,Li Gu,Michael X. Zhu,Shabnam Shalapour,Mojgan Hosseini,Gautam Bandyopadhyay,Su-Ling Zeng,Cristina Llorente,Haoqi Zhao,Santosh Lamichhane,Siddharth Mohan,Pieter C. Dorrestein,Jerrold M. Olefsky,Bernd Schnabl,Pejman Soroosh,Michael Karin
摘要
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.