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.

中文翻译：

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IL-22 通过肠上皮细胞 STAT3 恢复饮食扰动的肠道稳态来解决 MASLD


代谢功能障碍相关脂肪性肝病 （MASLD） 呈指数级增长，与能量密集型饮食的消费量不断增加相呼应，这凸显了对有效解决 MASLD 药物的需求。MASLD 的发病机制与肥胖、糖尿病、“肠-肝轴”改变和白细胞介素 22 （IL-22） 信号传导缺陷有关。尽管屏障保护性 IL-22 减弱了饮食诱导的代谢改变，抑制了脂质摄入，并逆转了微生物菌群失调，但致肥胖饮食会迅速抑制其由小肠定位的先天淋巴细胞的产生。这导致肠上皮细胞 （IEC） 中的 STAT3 抑制和吸收性肠上皮细胞区室的扩张。这些维持 MASLD 的畸变通过重组 IL-22 的给药而逆转，从而解决了肝脂肪变性、炎症、纤维化和胰岛素抵抗。外源性 IL-22 通过其 IEC 受体而不是肝细胞发挥其治疗作用，激活 STAT3 并抑制 WNT-β-catenin 信号传导以缩小吸收性肠上皮细胞区室。通过逆转饮食强化的宏量营养素吸收（肝脂的主要来源），IL-22 信号恢复代表了对膳食肥胖和 MASLD 的潜在有效拦截。