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Platelets accelerate endoplasmic reticulum stress and promote hepatic steatosis in mice

ABSTRACT: Background: Metabolic dysfunction-associated steatotic liver disease (MASLD), the most common chronic liver disease, is characterized by endoplasmic reticulum (ER) stress, which impairs hepatic lipoprotein metabolism. Platelets, which can modulate cellular responses to ER stress, accumulate in the liver during MASLD and contribute to disease development by interacting with liver-resident (immune) cells. Since the role of platelets in modulating hepatic ER stress in vivo is completely unknown, this study aims to investigate their effects on hepatic ER stress and steatosis. Methods/Results: Using C57BL/6 mice, we demonstrate that hepatic ER stress leads to the accumulation and activation of platelets. Depletion of platelets decreased ER stress-induced liver steatosis, indicated by reduced liver triglyceride levels. Mechanistically, we found that platelet depletion ameliorated the initial ER stress response and increased the influx of neutrophils into the liver. Inhibiting the platelet-specific receptor glycoprotein 1bα (GPIbα) partly mimicked the effects of platelet depletion, leading to impaired hepatic platelet recruitment and reduced triglyceride accumulation. Conclusion: This study demonstrates a new role of platelets in hepatic ER stress and the concomitant effect on hepatic steatosis.

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ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Blood Cell, Liver, Cell Culture

SUBMITTER: Ulrich Stelzl

LAB HEAD: Ulrich Stelzl

PROVIDER: PXD060292 | Pride | 2026-03-26

REPOSITORIES: Pride

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Project description:Background Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major cause of liver-related morbidity and mortality. Premenopausal women have a lower MASLD risk than postmenopausal women. G protein-coupled estrogen receptor 1 (GPER1) exerts hepatic protective effects, and GPER1 specific agonist (G1) has shown preclinical potential in improving metabolic disorders. However, clinical studies on G1’s metabolic benefits and GPER1’s clinical relevance in human liver tissue remain unclear. This study aims to bridge basic and clinical research by validating G1’s efficacy in ameliorating MASLD-related hepatic steatosis, exploring its molecular mechanisms, and clarifying GPER1’s association with human MASLD. Methods We investigated the expression of GPER1 in human liver tissue and its correlation with the severity of steatosis. The function of GPER1 was validated both in vitro (using a free fatty acid-induced hepatocyte steatosis model treated with the GPER1 agonist G1 or antagonist G15) and in vivo, with assessments of lipid metabolism-related genes, reactive oxygen species, and apoptosis. GPER1-associated proteins were identified through proteomic sequencing and co-immunoprecipitation. Results GPER1 is lowly expressed in MASLD patients, negatively correlating with steatosis severity. G1 upregulates GPER1, alleviates hepatocyte steatosis and lipid deposition, modulates lipid metabolism-related proteins, ameliorates hepatic steatosis, and interacts with GAIP-interacting protein C-terminal 1 (GIPC1). G15 antagonizes these beneficial effects. Conclusions Based on clinical data, this study shows that low GPER1 expression correlates closely with hepatic steatosis in MASLD. The GPER1 agonist G1 ameliorates hepatic steatosis via multiple GPER1-dependent mechanisms, including regulating lipid metabolism, suppressing oxidative stress, and reducing apoptosis. Notably, GIPC1 may be involved in the GPER1-mediated regulatory pathway, and its role in this context merits further investigation.

			Action	DRS
	MD_01_GA1_7526.d.zip	Other
	MD_01_GA1_7576.d.zip	Other
	MD_02_GA2_7528.d.zip	Other
	MD_02_GA2_7582.d.zip	Other
	MD_03_GA3_7530.d.zip	Other

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Platelets accelerate endoplasmic reticulum stress and promote hepatic steatosis in mice

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