肝细胞NLRP3与PKCε互作驱动肝脏胰岛素抵抗和脂肪变性  

Hepatocyte NLRP3 interacts with PKCεto drive hepatic insulin resistance and steatosis

作　　者：秦伟伟 翁建平 Weiwei Qin;Jianping Weng(Department of Endocrinology,Institute of Endocrine and Metabolic Diseases,The First Affiliated Hospital of USTC,Division of Life Sciences and Medicine,Clinical Research Hospital of Chinese Academy of Sciences(Hefei),University of Science and Technology of China,Hefei 230027,China)

机构地区：[1]Department of Endocrinology,Institute of Endocrine and Metabolic Diseases,The First Affiliated Hospital of USTC,Division of Life Sciences and Medicine,Clinical Research Hospital of Chinese Academy of Sciences(Hefei),University of Science and Technology of China,Hefei 230027,China

出　　处：《Science Bulletin》2023年第13期1413-1429,M0004,共18页科学通报（英文版）

基　　金：supported by the National Natural Science Foundation of China(82100867,81941022,and 81530025);the Anhui Provincial Natural Science Foundation(2108085QH323);the China Postdoctoral Science Foundation(2021M693104);the National Key R&D Program of China(2021YFC2500500);the Strategic Priority Research Program of Chinese Academy of Sciences(XDB38010100);the Program for Innovative Research Team of The First Affiliated Hospital of USTC(CXGG02)。

摘　　要：肝脏胰岛素抵抗(IR)是非酒精性脂肪性肝病(NAFLD)的重要特征之一,与肝脏脂肪变性密切相关.肝脏IR发病机制仍不清楚,本研究通过转录组学筛选鉴定到肝细胞NLRP3是肝脏IR的重要诱导因子,进一步证实其在人和小鼠NAFLD模型肝脏组织中表达增加.功能方面,肝细胞特异性NLRP3功能丧失或获得分别改善或加重高脂饮食(HFD)诱导的肝脏IR及脂肪变性.机制方面,NLRP3直接结合并促进蛋白激酶C蛋白(PKCs)的激活,从而损害胰岛素信号通路和增加肝脏脂肪变性;相反,抑制PKCe明显阻断HFD诱导的NLRP3缺陷小鼠的有益作用.此外,研究筛选发现转录因子阴阳1(YY1)调控NLRP3启动子.治疗方面,腺相关病毒血清型8介导的肝脏NLRP3敲低减轻瘦素受体缺陷(db/db)小鼠的肝脏IR和脂肪变性.同时,药理抑制NLRP3显著减轻饮食诱导的代谢紊乱.综上,本研究揭示了肝细胞NLRP3是肝脏IR和脂肪变性的直接驱动因素,并提示YY1-NLRP3-PKCε轴为NAFLD的潜在治疗靶点.Hepatic insulin resistance(IR),as a downstream sequela of nonalcoholic fatty liver disease(NAFLD),is strongly associated with liver steatosis.Despite numerous mechanism advancements,the molecular underpinnings and pathogenesis of hepatic IR,especially regarding the pattern recognition receptors in hepatocytes,remain elusive.Here,we identified hepatocyte NLRP3 as a direct and previously-unresolved driver of hepatic IR to promote steatosis response.Under the model of NAFLD,we identified hepatocyte NLRP3 as a crucial inducer of hepatic IR by undertaking multilayer transcriptomic searches and further confirmed that its expression was increased in the liver tissues from NAFLD patients and mouse models(high-fat diet(HFD),leptin-receptor-deficient(db/db)mice),and in palmitic acid(PA)-induced hepatocytes.Loss-or gain-of-function of hepatocyte-specific NLRP3 in HFD-induced mice ameliorated or exacerbated hepatic IR and steatosis,respectively.Mechanistically,NLRP3 directly bound to and promoted protein kinase C epsilon(PKCε)activation to impair insulin signaling and increase liver steatosis,while inhibition of PKCεactivation dampened the beneficial effects seen in HFD-induced NLRP3-deficient mice.Moreover,we performed screening and discovered that the transcription factor Yin Yang 1(YY1)positively controlled NLRP3 expression.In translational potential,adeno-associated virus serotype 8(AAV8)-mediated NLRP3 knockdown in the liver alleviated hepatic IR and steatosis in db/db mice,and pharmacological inhibition of NLRP3 markedly alleviated diet-induced metabolic disorders.This finding reveals a previously-unexpected regulatory axis from YY1 to PKCεvia NLRP3 induction for metabolic diseases and establishes the YY1-NLRP3-PKCεaxis as a potential therapeutic target for NAFLD.

关 键 词：NLRP3 Hepatic IR NAFLD PKCΕ 

分 类 号：R575[医药卫生—消化系统]