Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury
Interleukin-22 drives a metabolic adaptive reprogramming to maintain mitochondrial fitness and treat liver injury
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Interleukin-22 驱动代谢适应性重编程以维持线粒体健康并治疗肝损伤
DOI：
10.7150/thno.43894
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Ju, Dianwen
中科院分区：
文献类型：
--
作者：
Chen, Wei;Zai, Wenjing;Ju, Dianwen
理论基础：白介素22(IL-22)是一种上皮细胞存活细胞因子，目前正在探索作为急慢性肝损伤的治疗剂。然而，其保护作用的分子基础尚不清楚。方法：我们证明了IL-22能抑制由刺激引起的肝细胞代谢状态的恶化。利用细胞生物学、分子和生化方法，我们提供了IL-22促进氧化磷酸化(OXPHOS)和糖酵解并调节代谢重编程相关的转录反应的证据。结果：IL-22通过诱导AMP激活的蛋白激酶(AMPK)、AKT和哺乳动物雷帕霉素靶点(MTOR)来调控代谢调节器和酶的活性，从而改善线粒体功能障碍。上游效应子lncRNA H19也参与了肝细胞中这些代谢过程的控制。重要的是，在顺铂诱导的肝损伤和脂肪性肝炎中，进一步证实了IL-22通过激活代谢相关信号和调节线粒体功能来改善肝损伤。结论：综上所述，我们的结果揭示了IL-22在肝损伤过程中调节肝细胞代谢的新机制，为临床治疗和预防肝病提供了有益的启示。
Rationale: Interleukin 22 (IL-22) is an epithelial survival cytokine that is at present being explored as therapeutic agents for acute and chronic liver injury. However, its molecular basis of protective activities remains poorly understood.Methods: Here we demonstrate that IL-22 inhibits the deteriorating metabolic states induced by stimuli in hepatocytes. Utilizing cell biological, molecular, and biochemical approaches, we provide evidence that IL-22 promotes oxidative phosphorylation (OXPHOS) and glycolysis and regulates the metabolic reprogramming related transcriptional responses.Results: IL-22 controls metabolic regulators and enzymes activity through the induction of AMP-activated protein kinase (AMPK), AKT and mammalian target of rapamycin (mTOR), thereby ameliorating mitochondrial dysfunction. The upstream effector lncRNA H19 also participates in the controlling of these metabolic processes in hepatocytes. Importantly, amelioration of liver injury by IL-22 through activation of metabolism relevant signaling and regulation of mitochondrial function are further demonstrated in cisplatin-induced liver injury and steatohepatitis.Conclusions: Collectively, our results reveal a novel mechanism underscoring the regulation of metabolic profiles of hepatocytes by IL-22 during liver injury, which might provide useful insights from the bench to the clinic in treating and preventing liver diseases.