Deficiency of gluconeogenic enzyme PCK1 promotes metabolic-associated fatty liver disease through PI3K/AKT/PDGF axis activation in male mice

作者全名："Ye, Qian; Liu, Yi; Zhang, Guiji; Deng, Haijun; Wang, Xiaojun; Tuo, Lin; Chen, Chang; Pan, Xuanming; Wu, Kang; Fan, Jiangao; Pan, Qin; Wang, Kai; Huang, Ailong; Tang, Ni"

作者地址："[Ye, Qian; Liu, Yi; Zhang, Guiji; Deng, Haijun; Pan, Xuanming; Wu, Kang; Wang, Kai; Huang, Ailong; Tang, Ni] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Infect Dis, Chongqing, Peoples R China; [Wang, Xiaojun] Army Med Univ, Mil Med Univ 3, Southwest Hosp, Inst Hepatobiliary Surg, Chongqing, Peoples R China; [Tuo, Lin] Univ Elect Sci & Technol China, Hosp, Dept Infect Dis, Chengdu, Peoples R China; [Chen, Chang] Chongqing Med Univ, Inst Life Sci, Chongqing, Peoples R China; [Fan, Jiangao; Pan, Qin] Shanghai Jiao Tong Univ, Sch Med, Xin Hua Hosp, Dept Gastroenterol, Shanghai, Peoples R China"

通信作者："Wang, K; Huang, AL; Tang, N (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Infect Dis, Chongqing, Peoples R China."

来源：NATURE COMMUNICATIONS

ESI学科分类：　

WOS号：WOS:001055247000013

JCR分区：Q1

影响因子：14.7

年份：2023

卷号：14

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："Metabolic associated fatty liver disease (MAFLD) encompasses a broad spectrum of hepatic disorders, including steatosis, nonalcoholic steatohepatitis (NASH) and fibrosis. We demonstrated that phosphoenolpyruvate carboxykinase 1 (PCK1) plays a central role in MAFLD progression. Male mice with liver Pck1 deficiency fed a normal diet displayed hepatic lipid disorder and liver injury, whereas fibrosis and inflammation were aggravated in mice fed a high-fat diet with drinking water containing fructose and glucose (HFCD-HF/G). Forced expression of hepatic PCK1 by adeno-associated virus ameliorated MAFLD in male mice. PCK1 deficiency stimulated lipogenic gene expression and lipid synthesis. Moreover, loss of hepatic PCK1 activated the RhoA/PI3K/AKT pathway by increasing intracellular GTP levels, increasing secretion of platelet-derived growth factor-AA (PDGF-AA), and promoting hepatic stellate cell activation. Treatment with RhoA and AKT inhibitors or gene silencing of RhoA or AKT1 alleviated MAFLD progression in vivo. Hepatic PCK1 deficiency may be important in hepatic steatosis and fibrosis development through paracrine secretion of PDGF-AA in male mice, highlighting a potential therapeutic strategy for MAFLD. Phosphoenolpyruvate carboxykinase 1 (Pck1) is an enzyme involved in glucose production that also regulates lipogenesis and has been linked to liver steatosis. Here the authors report that deficiency of Pck1 in the liver leads to nonalcoholic fatty liver disease via activation of the RhoA/PI3K/AKT pathway in a study with male mice."

基金机构："National Natural Science Foundation of China [U20A20392, 82073251, 82273238, 82072286, 82272975]; 111 Project [D20028]; Natural Science Foundation Project of Chongqing [cstc2018jcyjAX0254, cstc2019jscx-dxwtBX0019]; Science and Technology Research Program of Chongqing Municipal Education Commission [HZ2021006, KJZD-M202000401]; Future Medical Youth Innovation Team of Chongqing Medical University [W0036, W0101]; Kuanren talents program of the second affiliated hospital of Chongqing Medical University; Scientific Research Innovation Project for Postgraduate in Chongqing [CYB19168, CYS19193]; Youth talent fund of Sichuan Provincial People's Hospital in 2020 [2020QN03]"

基金资助正文："We would like to thank Dr. T.-C He (University of Chicago, USA) and Prof. Ding Xue (Tsinghua University, China) for providing the pAdEasy and CRISPR/Cas9 system, respectively. We thank Prof. Youde Cao and Yalan Wang (Chongqing Medical University, China) for providing samples and pathological analysis support. We thank Prof. Yongjun Dang, Hui Zhou and Luyi Huang (Chongqing Medical University, China) for providing the strong technical support for measuring intracellular GTP levels. This work was supported by the National Natural Science Foundation of China (grant no. U20A20392, 82073251, 82273238, 82072286, 82272975), the 111 Project (No. D20028), the Natural Science Foundation Project of Chongqing (cstc2018jcyjAX0254, cstc2019jscx-dxwtBX0019), the Science and Technology Research Program of Chongqing Municipal Education Commission (HZ2021006, KJZD-M202000401), the Future Medical Youth Innovation Team of Chongqing Medical University (W0036, W0101), the Kuanren talents program of the second affiliated hospital of Chongqing Medical University, the Scientific Research Innovation Project for Postgraduate in Chongqing (CYB19168, CYS19193), and the Youth talent fund of Sichuan Provincial People's Hospital in 2020 (No. 2020QN03)."