Metabolic dysfunction-associated steatohepatitis (MASH) significantly increases the risk of liver cirrhosis and hepatocellular carcinoma. While Fibroblast Growth Factor 21 (FGF21) analogs have shown promise in clinical trials, their underlying molecular mechanisms remain unclear.
A research team led by Prof. LI Yu at the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences identified a novel mechanism in understanding the therapeutic mechanism of FFGF21 in treating liver fibrosis and MASH via the protein phosphatase PPP6C. This study was published online in Journal of Hepatology.
By establishing a diet-induced MASH model, researchers found that hepatocyte-specific knockout of βKlotho significantly blocked the improvement of MASH by FGF21, confirming that FGF21 ameliorated MASH progression through the autocrine signaling pathway mediated by the FGFR/βKlotho receptor complex in hepatocytes.
By employing protein interaction mass spectrometry screening, researchers identified that the protein phosphatase PPP6C can directly bind to βKlotho. This means that the absence of PPP6C blocked the therapeutic effects of FGF21 on MASH.
Mechanistically, the FGF21/βKlotho signaling pathway activated PPP6C phosphatase activity, which recruited and mediated the dephosphorylation of TSC2 at Ser939 and Thr1462, thereby inhibiting mTORC1 activity and promoting the nuclear translocation of transcription factors TFE3 and Lipin1.
Moreover, researchers found that PPP6C expression levels were significantly reduced in liver tissues from both clinical patients and mouse models of MASH, indicating that PPP6C may act as a negative regulator of MASH progression in mice and humans.
The study demonstrates that pharmacological administration of FGF21 protects against MASH pathology at least in large through the interaction between βKlotho and PPP6C and PPP6C-mediated dephosphorylation of TSC2 in hepatocytes. It advances the understanding of FGF21 signals in hepatocytes and demonstrates that targeting PPP6C may have therapeutic potential for treating liver fibrosis and MASH.
The proposed model for FGF21-activated PPP6C in treating liver Fibrosis and metabolic dysfunction-associated steatohepatitis. (Image by Prof. LI Yu's group)
