美国加州大学圣迭戈分校Michael Karin研究小组发现，IL-22通过肠上皮细胞STAT3介导的饮食干扰肠道稳态恢复来缓解MASLD。2024年9月23日，《细胞—代谢》杂志在线发表了这项成果。

研究人员表示，代谢功能障碍相关脂肪性肝病（MASLD）的指数增长与能量密集型饮食的不断增加密切相关，这突显了开发有效的MASLD解决药物的必要性。MASLD的发病机制与肥胖、糖尿病、“肠-肝轴”变化及缺陷的白细胞介素-22（IL-22）信号传导相关。

研究人员发现，尽管具有保护屏障功能的IL-22可以减弱饮食引起的代谢变化、抑制脂质摄入并逆转微生物失调，但肥胖饮食会迅速抑制小肠局部的先天淋巴细胞产生IL-22。这导致肠上皮细胞（IEC）中STAT3的抑制和吸收性肠上皮细胞群体的扩展。

这些维持MASLD的异常现象通过重组IL-22的给药得以逆转，从而消除了肝脏脂肪变性、炎症、纤维化和胰岛素抵抗。外源性IL-22通过其在IEC上的受体而非肝细胞发挥治疗作用，激活STAT3并抑制WNT-β-联蛋白信号传导，从而缩小吸收性肠上皮细胞群体。通过逆转饮食强化的宏量营养素吸收，IL-22信号的恢复代表了对饮食性肥胖和MASLD的潜在有效干预。

附：英文原文

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

Author: 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

Issue&Volume: 2024-09-23

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.

DOI: 10.1016/j.cmet.2024.08.012

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00364-4