AMPK maintains the activation of hepatic stellate cells through mitophagy-induced metabolic reprogramming

Published Sep 4, 2025Journal of molecular cell biology

AMPK helps keep liver support cells active by changing their metabolism through recycling damaged mitochondria

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Abstract

Phosphorylation of AMPK in hepatic stellate cells was found to be upregulated in liver tissues from patients with metabolic dysfunction-associated steatohepatitis.

The activation of hepatic stellate cells (HSCs) is a key process in liver fibrosis, involving their transdifferentiation from a resting state to a fibrogenic phenotype.
In mouse models, deletion of two catalytic α-subunits of AMPK in HSCs reduced liver fibrosis caused by carbon tetrachloride or bile duct ligation.
AMPK activation in HSCs enhances their activation in response to profibrogenic stimuli, indicating its role in energy management during fibrosis progression.
Deficiency in AMPKα impairs mitochondrial function in HSCs, but this can be restored with treatment using the mitophagy inducer rapamycin.
Both AMPK-ULK1 and AMPK-Raptor pathways are involved in regulating mitophagy and maintaining mitochondrial health in activated HSCs.

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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 catalytic α-subunits of AMPK attenuated liver fibrosis in the CCl4 or BDL mouse model. In vitro analysis demonstrated that AMPK promoted HSC activation when challenged with 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.

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AMPK maintains the activation of hepatic stellate cells through mitophagy-induced metabolic reprogramming

Abstract

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