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

• Published in: Nature communications Vol. 14; no. 1; pp. 1402 - 19
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.03.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/1; 13/51; 13/89; 13/95; 14/34; 14/63; 140/58; 38/1; 38/109; 38/77; 38/91; 45/15; 631/80/86/2341; 64/60; 692/4020/4021/1607/2751; 82/80; AKT protein; AKT1 protein; Animals; Cell activation; Diet; Diet, High-Fat - adverse effects; Drinking water; Enzymes; Fatty liver; Fibrosis; Gene expression; Gene silencing; Glucose; Growth factors; High fat diet; Humanities and Social Sciences; Lipids; Lipogenesis; Liver; Liver - metabolism; Liver Cirrhosis - pathology; Liver diseases; Male; Males; Metabolic rate; Metabolism; Mice; Mice, Inbred C57BL; multidisciplinary; Non-alcoholic Fatty Liver Disease - metabolism; Paracrine signalling; Phosphatidylinositol 3-Kinases - metabolism; Phosphoenolpyruvate Carboxykinase (GTP) - genetics; Platelet-derived growth factor; Proto-Oncogene Proteins c-akt - metabolism; RhoA protein; Science; Science (multidisciplinary); Secretion; Steatosis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-37142-3

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.