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Shanghai, China – A groundbreaking study led by Prof. Li Yu at the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences has identified a novel mechanism in the treatment of liver fibrosis and metabolic dysfunction-associated steatohepatitis (MASH). The research sheds light on the molecular workings of fibroblast growth factor 21 (FGF21) analogs, which have shown promise in clinical trials.
MASH significantly increases the risk of liver cirrhosis and hepatocellular carcinoma, making it a pressing health concern. Despite the therapeutic potential of FGF21, its precise molecular mechanisms have remained elusive—until now.
The study, published in the Journal of Hepatology, explores the role of the protein phosphatase PPP6C in mediating FGF21’s effects. Researchers used a diet-induced MASH model and found that knocking out βKlotho in hepatocytes blocked FGF21’s ability to improve MASH. This confirmed that FGF21 exerts its protective effects through an autocrine signaling pathway involving the FGFR/βKlotho receptor complex in hepatocytes.
By employing protein interaction mass spectrometry, the team discovered that PPP6C binds directly to βKlotho. The absence of PPP6C negated FGF21’s therapeutic effects, highlighting its crucial role in liver health. Further analysis showed that the FGF21/βKlotho pathway activates PPP6C phosphatase activity, which in turn regulates TSC2 dephosphorylation at Ser939 and Thr1462, inhibiting mTORC1 activity. This process promotes nuclear translocation of transcription factors TFE3 and Lipin1, which are essential in controlling MASH progression.
Notably, PPP6C expression was found to be significantly reduced in liver tissues from both MASH patients and mouse models, suggesting that PPP6C acts as a key regulatory factor in disease progression. The findings indicate that targeting PPP6C could be a potential therapeutic strategy for treating liver fibrosis and MASH.
The study advances our understanding of how FGF21 functions in hepatocytes and underscores the importance of PPP6C as a novel target for future treatments. As researchers continue exploring these molecular pathways, the prospect of more effective therapies for liver diseases becomes increasingly tangible.
Disclaimer: This article is for informational purposes only and does not constitute medical advice. Readers should consult healthcare professionals for medical concerns or treatment options.
