GPER Ameliorates Mitochondrial Dysfunction in Sepsis-induced Hepatocytes via Activating the AMPK-PDHA1/CPT1B Pathway

doi:10.3870/j.issn.1672-0741.25.08.013

Abstract

Abstract: Objective To investigate the possible mechanism by which G protein-coupled estrogen receptor(GPER)improves mitochondrial dysfunction in the hepatocytes of patients with sepsis. Methods An in vitro sepsis model was established by stimulating AML-12 hepatocytes with lipopolysaccharide(LPS).The cells were divided into four groups:control,LPS-treated,LPS + G1(a GPER agonist),and LPS + G15(a GPER antagonist)groups.Cell viability,apoptosis,the levels of inflammatory factors(TNF-α,IL-1β,and IL-6),and energy metabolism indicators(ATP/AMP)were assessed via techniques such as CCK-8,flow cytometry,and ELISA.The mRNA and protein expression levels of GPER were determined by RT-qPCR and Western blotting respectively.Western blot analysis was also employed to examine AMPK phosphorylation(p-AMPK)and the protein expression of pyruvate dehydrogenase E1 alpha subunit(PDHA1)and carnitine palmitoyltransferase 1B(CPT1B).Mitochondrial reactive oxygen species(mtROS)and mitochondrial membrane potential(ΔΨm)were measured via laser scanning confocal microscopy and flow cytometry,respectively.The ultrastructure of the mitochondria was observed via transmission electron microscopy. Results In the LPS-induced hepatocyte sepsis model,the GPER agonist G1 not only significantly improved cell viability,inhibited apoptosis,and reduced inflammatory responses but also effectively reversed energy metabolism disorders,decreased oxidative stress(all P<0.01),and repaired mitochondrial ultrastructural damage.In contrast,the GPER antagonist G15 not only completely abolished the protective effects of G1 but also further exacerbated these damage indicators(all P<0.01). Conclusion GPER protects against sepsis-induced hepatocyte injury via activating the AMPK-PDHA1/CPT1B axis,which enhances glucose and lipid metabolism,preserves mitochondrial energy homeostasis,and mitigates oxidative stress.These findings suggest that GPER is a potential novel target for sex-specific therapeutic strategies in sepsis.

Key words: G protein-coupled estrogen receptor, AMP-activated protein kinase, pyruvate dehydrogenase E1 alpha subunit, carnitine palmitoyltransferase 1B, sepsis, mitochondrial dysfunction

CLC Number:

R515.3

Yang Leilei, Peng Jian, Feng Xiaojing et al. GPER Ameliorates Mitochondrial Dysfunction in Sepsis-induced Hepatocytes via Activating the AMPK-PDHA1/CPT1B Pathway[J]. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong, 2026, 55(1): 61-67.

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