| 论文作者 |
Liu, ZS; Wei, S; Jiang, Y; Su, WT; Ma, FG; Cai, GX; Liu, YX; Sun, XY; Lu, L; Fu, WG; Xu, Y; Huang, RJ; Li, J; Lin, X; Cui, AY; Zang, MW; Xu, AM; Li, Y |
| 摘要 |
Background & Aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a serious chronic liver disease for which therapeutic options are limited. Although fibroblast growth factor 21 (FGF21) analogs have shown therapeutic promise for MASH in multiple preclinical and clinical studies, their underlying mechanisms of action remain elusive. Methods: Liver-specific PPP6C and bKlotho knockout mice and their wild-type littermates were fed an AMLN (Amylin liver NASH) diet for 16 weeks or a CDA-HFD (choline-deficient, L-amino acid-defined, high-fat diet) for 8 weeks, followed by daily subcutaneous injection of recombinant FGF21 (0.5 mg/kg) or vehicle for 4 weeks. A mass spectrometry assay identified PPP6C as a bKlotho-binding protein. An in vitro phosphatase assay was used to evaluate the effects of FGF21 on PPP6C activity. PPP6C expression was also analyzed in human samples from patients with MASH. Results: We identified serine and threonine phosphatase PPP6C as a direct target of FGF21. Hepatic PPP6C deficiency accelerates MASH progression in mice fed an AMLN diet or CDA-HFD, which blocks the effect of FGF21 on MASH. Mechanistically, PPP6C is sufficient to interact with the coreceptor bKlotho upon FGF21 treatment and directly dephosphorylates tuberous sclerosis complex 2 (TSC2) at Ser939 and Thr1462, thereby inhibiting mTORC1 and promoting nuclear entry of TFE3 and Lipin1. In the livers of patients with MASH, expression levels of PPP6C are decreased whereas TSC2 phosphorylation is elevated. Conclusions: PPP6C acts as a fundamental downstream mediator essential for FGF21 signaling in hepatocytes and targeting PPP6C by FGF21 may offer therapeutic potential for treating MASH in humans. (c) 2025 European Association for the Study of the Liver. Published by Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies. |
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