AbstractBackground and AimsNonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by hepatic lipid accumulation, inflammation, and progressive fibrosis. However, the pathomechanisms underlying NASH are incompletely explored. Phosphoenolpyruvate carboxykinase 1 (PCK1) catalyzes the first rate-limiting step of gluconeogenesis in the cytoplasm. This study was designed to determine the role of PCK1 in regulating NASH progression.MethodsLiver metabolism, hepatic steatosis, and fibrosis were evaluated at 24 weeks in liver-specific Pck1-knockout (L-KO) mice fed with NASH diet (high fat diet with ad libitum consumption of water containing glucose and fructose). AKT and RhoA inhibitors were evaluated for disease treatment in L-KO mice fed NASH diet.ResultsPCK1 is downregulated in patients with NASH and mouse models of NASH. L-KO mice displayed hepatic lipid disorder and liver injury fed with normal diet, while fibrosis and inflammation were aggravated when fed NASH diet. Mechanistically, transcriptome analysis revealed PCK1 deficiency upregulated genes involved in fatty acid transport and lipid droplet formation. Moreover, untargeted metabolomics analysis showed the accumulation of glycerol 3-phosphate, the substrate of triglyceride synthesis. Furthermore, the loss of PCK1 could activate the RhoA/PI3K/AKT pathway, which leads to increased secretion of PDGF-AA and promotes the activation of hepatic stellate cells. RhoA and AKT inhibitors alleviated NASH progression in L-KO mice fed NASH diet.ConclusionsPCK1 deficiency plays a key role in the development of hepatic steatosis and fibrosis by facilitating the RhoA/PI3K/AKT/PDGF-AA axis. These findings provide a novel insight into therapeutic approaches for the treatment of NASH.Lay summaryNon-alcoholic steatohepatitis (NASH) is currently the most common chronic liver disease, which is correlated with progressing chronic disorder of lipid metabolism and a persistent inflammatory response. In the present study, decreased PCK1 is observed in patients with NASH and mouse NASH models, and its loss aggravates steatohepatitis in NASH mice fed high-fat, high-fructose diet by stimulating expression of lipogenic genes and lipid synthesis. Inhibitors of proteins involved in the underlying molecular process alleviated the liver disease, highlighting a new therapeutic strategy for NASH.Graphical abstractHighlightsGluconeogenic enzyme PCK1 is downregulated in both human patients and NASH mice.PCK1 depletion promotes hepatic steatosis by dysregulating lipid metabolism and synthesis.PCK1 loss promotes hepatic fibrosis by activating RhoA/PI3K/AKT/PDGF-AA axis.Targeting RhoA/AKT alleviates NASH progression in liver-specific Pck1-knockout mice.
Correction: Factors Affecting the Accuracy of Controlled Attenuation Parameter (CAP) in Assessing Hepatic Steatosis in Patients with Chronic Liver Disease
