摘要
The activation of hepatic stellate cells(HSCs),characterized by transdifferentiation from a quiescent state to a fibrogenic phenotype,is a core process of liver fibrosis.The metabolic reprogramming of HSCs plays a major role in this process to meet the high energy demands of myofibroblastic HSCs with multiple functions,such as extracellular matrix synthesis,migration,and proliferation.AMP-activated protein kinase(AMPK)is a gatekeeper of intracellular energy homeostasis,but its role in the activation of HSCs and the progression of liver fibrosis remains unclear.Here,we found that the phosphorylation of AMPK in HSCs was upregulated in liver tissues from metabolic dysfunction-associated steatohepatitis patients and from mice treated with carbon tetrachloride(CCl4)or bile duct ligation(BDL).HSC-specific deletion of two catalyticα-subunits of AMPK attenuated liver fibrosis in the CCl4 or BDL mouse model.In vitro analysis demonstrated that AMPK promoted HSC activation upon various profibrogenic stimuli.The activation of AMPKα-deficient HSCs was impaired due to the decreased mitochondrial oxidative phosphorylation but restored after treatment with the mitophagy inducer rapamycin.Mechanistically,both the AMPK–ULK1 and AMPK–Raptor pathways contribute to the maintenance of the mitophagy pathway and mitochondrial quality.These findings provide direct evidence of the crucial role of AMPK–mitophagy signaling in ensuring mitochondrial health and sufficient energy supply during HSC activation.In this study,AMPK was modulated in HSCs prior to activation,which is distinguished from previous investigations and thus provides new insights into the role of AMPK during distinct phases of HSC activation.
基金
supported by grants from the National Natural Science Foundation of China(82130099 to J.L.)
the Key New Drug Creation and Manufacturing Program of China(2019zX09201001-003-010 to Y.Z.)
Shanghai Institute of Materia Medica(CASIMM0120225006-2 to J.L.)
Taishan Scholar Foundation of Shandong Province(tstp0648 to J.L.)
the Natural Science Foundation of Shandong Province(ZR2024QC378 to Hanmin Wang).
