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Deficiency of gluconeogenic enzyme PCK1 promotes non-alcoholic steatohepatitis progression by activation of PI3K/AKT/PDGF axis

Ye, Q.; Liu, Y.; Zhang, G.; Deng, H.; Chen, C.; Pan, X.; Wu, K.; Fan, J.; Pan, Q.; Wang, K.; Huang, A.; Tang, N.

2021-01-12 molecular biology
10.1101/2021.01.12.426294 bioRxiv
Show abstract

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by hepatic lipid accumulation, inflammation, and progressive fibrosis. We demonstrated that phosphoenolpyruvate carboxykinase 1 (PCK1) plays a central role in NASH progression. 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 NASH diet. Forced expression of PCK1 by adeno-associated virus in the liver ameliorated NASH in 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 NASH progression in vivo. Hepatic PCK1 deficiency may be important in hepatic steatosis and fibrosis development through paracrine secretion of PDGF-AA, highlighting a therapeutic strategy for NASH.

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"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.