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

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

  • Nat Commun. 2023 Mar 14;14(1):1402. doi: 10.1038/s41467-023-37142-3.
Qian Ye # 1,  Yi Liu # 1,  Guiji Zhang # 1,  Haijun Deng # 1,  Xiaojun Wang # 2,  Lin Tuo # 3,  Chang Chen 4,  Xuanming Pan 1,  Kang Wu 1,  Jiangao Fan 5,  Qin Pan 5,  Kai Wang 6,  Ailong Huang 7,  Ni Tang 8
Affiliations

Affiliations

  • 1 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
  • 2 Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China.
  • 3 Department of Infectious Disease, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China.
  • 4 Institute of Life Sciences, Chongqing Medical University, Chongqing, China.
  • 5 Department of Gastroenterology, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 6 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. wangkai@cqmu.edu.cn.
  • 7 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. ahuang@cqmu.edu.cn.
  • 8 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China. nitang@cqmu.edu.cn.
  • # Contributed equally.
PMID: 36918564 DOI: 10.1038/s41467-023-37142-3
Abstract

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.

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