New Insights into Treating Liver Fibrosis and Metabolic Disorders

Recent research has unveiled a significant mechanism for treating liver fibrosis and metabolic dysfunction-associated steatohepatitis (MASH), conditions that heighten the risk of severe liver diseases such as cirrhosis and hepatocellular carcinoma.

The study, conducted by a team from the Shanghai Institute of Nutrition and Health, part of the Chinese Academy of Sciences, sheds light on the role of fibroblast growth factor 21 (FGF21) and its analogs, which have shown promise in clinical trials but lacked clarity regarding their molecular workings.

Through the development of a diet-induced MASH model, researchers discovered that the absence of the ?Klotho protein in hepatocytes significantly hindered the therapeutic effects of FGF21, indicating that FGF21 counteracts MASH progression through an autocrine signaling pathway linked to the FGFR/?Klotho receptor complex.

Advanced protein interaction mass spectrometry screening enabled the identification of the protein phosphatase PPP6C, which directly binds to ?Klotho. The blockade of PPP6C was found to negate the beneficial effects of FGF21 on MASH, emphasizing its critical role in the treatment process.

Mechanistically, the FGF21/?Klotho signaling pathway activates the phosphatase activity of PPP6C, which leads to the dephosphorylation of TSC2 at specific sites, effectively inhibiting mTORC1 activity. This process facilitates the nuclear translocation of important transcription factors TFE3 and Lipin1, which are vital for cellular regulation.

Moreover, the study revealed a notable reduction in the expression levels of PPP6C in liver tissues from both clinical patients and mouse models suffering from MASH. This suggests that PPP6C might function as a negative regulator in the progression of MASH in both humans and mice.

In conclusion, this research illustrates that the pharmacological administration of FGF21 can provide protection against MASH pathology, primarily through the interaction between ?Klotho and PPP6C, as well as the PPP6C-mediated dephosphorylation of TSC2 in hepatocytes. The findings enhance the understanding of FGF21 signaling in liver cells and suggest that targeting PPP6C could offer a new therapeutic avenue for managing liver fibrosis and MASH.