小柯机器人

美国辛辛那提大学医学院Senad Divanovic研究小组近日取得一项新成果。经过不懈努力，他们的最新研究探明了肝脏Th17细胞pkm2依赖性代谢调节非酒精性脂肪肝（NAFLD）的发病机制。相关论文于2021年5月17日在线发表于国际学术期刊《细胞-代谢》杂志。

研究人员发现并表征了可加剧NAFLD发病的炎性肝CXCR3⁺ Th17（ihTh17）特异性细胞亚群。肝ihTh17细胞的累积取决于肝脏微环境和CXCR3通路的激活。从机制上讲，ihTh17细胞的致病潜力与染色质可及性、糖酵解输出以及IL-17A、IFNγ和TNFα的产生增加有关。使用2-DG或细胞特异性PKM2敲除调节糖酵解足以逆转以ihTh17为中心的炎症症状和NAFLD严重性。

重要的是，ihTh17细胞特性、CXCR3通路激活和肝糖酵解基因表达在人NAFLD中也是保守的。总之，该数据表明，脂肪变性的肝脏微环境调节Th17细胞的累积、代谢和竞争性干扰ihTh17的命运决定。对这些途径的调节具有开发新NAFLD治疗策略的潜能。

据悉，越来越多的证据表明Th17细胞在非酒精性脂肪性肝的发病过程中起关键作用。然而，肝脏Th17细胞的致病特性和机制仍然未知。

附：英文原文

Title: PKM2-dependent metabolic skewing of hepatic Th17 cells regulates pathogenesis of non-alcoholic fatty liver disease

Author: Maria E. Moreno-Fernandez, Daniel A. Giles, Jarren R. Oates, Calvin C. Chan, Michelle S.M.A. Damen, Jessica R. Doll, Traci E. Stankiewicz, Xiaoting Chen, Kashish Chetal, Rebekah Karns, Matthew T. Weirauch, Lindsey Romick-Rosendale, Stavra A. Xanthakos, Rachel Sheridan, Sara Szabo, Amy S. Shah, Michael A. Helmrath, Thomas H. Inge, Hitesh Deshmukh, Nathan Salomonis, Senad Divanovic

Issue&Volume: 2021-05-17

Abstract: Emerging evidence suggests a key contribution to non-alcoholic fatty liver disease(NAFLD) pathogenesis by Th17 cells. The pathogenic characteristics and mechanismsof hepatic Th17 cells, however, remain unknown. Here, we uncover and characterizea distinct population of inflammatory hepatic CXCR3+Th17 (ihTh17) cells sufficient to exacerbate NAFLD pathogenesis. Hepatic ihTh17 cellaccrual was dependent on the liver microenvironment and CXCR3 axis activation. Mechanistically,the pathogenic potential of ihTh17 cells correlated with increased chromatin accessibility,glycolytic output, and concomitant production of IL-17A, IFNγ, and TNFα. Modulationof glycolysis using 2-DG or cell-specific PKM2 deletion was sufficient to reverseihTh17-centric inflammatory vigor and NAFLD severity. Importantly, ihTh17 cell characteristics,CXCR3 axis activation, and hepatic expression of glycolytic genes were conserved inhuman NAFLD. Together, our data show that the steatotic liver microenvironment regulatesTh17 cell accrual, metabolism, and competence toward an ihTh17 fate. Modulation ofthese pathways holds potential for development of novel therapeutic strategies forNAFLD.

DOI: 10.1016/j.cmet.2021.04.018

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(21)00216-3

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