The proposed mannequin for FGF21-activated PPP6C in treating liver Fibrosis and metabolic dysfunction-associated steatohepatitis. Credit score: Prof. Li Yu’s group
Metabolic dysfunction-associated steatohepatitis (MASH) considerably will increase the chance of liver cirrhosis and hepatocellular carcinoma. Whereas fibroblast progress issue 21 (FGF21) analogs have proven promise in medical trials, their underlying molecular mechanisms stay unclear.
A analysis workforce led by Prof. Li Yu on the Shanghai Institute of Vitamin and Well being of the Chinese language Academy of Sciences recognized a novel mechanism in understanding the therapeutic mechanism of FGF21 in treating liver fibrosis and MASH by way of the protein phosphatase PPP6C.
This examine was revealed on-line within the Journal of Hepatology.
By establishing a diet-induced MASH mannequin, researchers discovered that hepatocyte-specific knockout of βKlotho considerably blocked the development of MASH by FGF21, confirming that FGF21 ameliorated MASH development via the autocrine signaling pathway mediated by the FGFR/βKlotho receptor advanced in hepatocytes.
By using protein interplay mass spectrometry screening, researchers recognized that the protein phosphatase PPP6C can immediately bind to βKlotho. Which means that the absence of PPP6C blocked the therapeutic results of FGF21 on MASH.
Mechanistically, the FGF21/βKlotho signaling pathway activated PPP6C phosphatase exercise, which recruited and mediated the dephosphorylation of TSC2 at Ser939 and Thr1462, thereby inhibiting mTORC1 exercise and selling the nuclear translocation of transcription components TFE3 and Lipin1.
Furthermore, researchers discovered that PPP6C expression ranges have been considerably decreased in liver tissues from each medical sufferers and mouse fashions of MASH, indicating that PPP6C might act as a damaging regulator of MASH development in mice and people.
The examine demonstrates that pharmacological administration of FGF21 protects in opposition to MASH pathology no less than in giant via the interplay between βKlotho and PPP6C and PPP6C-mediated dephosphorylation of TSC2 in hepatocytes.
It advances the understanding of FGF21 indicators in hepatocytes and demonstrates that concentrating on PPP6C might have therapeutic potential for treating liver fibrosis and MASH.
Extra info:
Zhengshuai Liu et al, Protein phosphatase 6 regulates metabolic dysfunction-associated steatohepatitis by way of the mTORC1 pathway, Journal of Hepatology (2025). DOI: 10.1016/j.jhep.2025.02.003
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Chinese language Academy of Sciences
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Treating liver fibrosis and metabolic dysfunction-associated steatohepatitis: Analysis identifies novel mechanism (2025, February 18)
retrieved 18 February 2025
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