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Rapamycin-induced fatty liver in mice is attenuated by chloroquine co-treatment in an ERR⍺-dependent manner

ABSTRACT: Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), remains a major health concern world-wide. Hepatic steatosis manifests by the aberrant accumulation of lipids in hepatocytes. We have previously shown that pharmacological inhibition of autophagy repressor mTOR complex 1 (mTORC1) by rapamycin, a widely utilized potent immunosuppressant, induces MASLD under normal conditions. Notably, this phenotype was found exacerbated in mice with genetic or pharmacological inhibition of the master transcriptional regulator of energy metabolism, nuclear receptor ERR⍺. In this study, we show that combining autophagy inhibitor chloroquine with the autophagy inducer rapamycin attenuates the severity of hepatic lipid deposition observed with rapamycin monotherapy. Bulk mRNA-seq profiling showed that chloroquine co-injection reverses the upregulation of a large proportion of genes linked to lipid metabolism homeostasis found induced by rapamycin alone. Interrogation of these genes for direct transcriptional regulators identified ERR⍺ among top candidates. Using a mouse model with genetic ERR⍺ ablation, we demonstrate a crucial dependency on ERR⍺ activity for the observed amelioration of rapamycin-induced hepatic steatosis by chloroquine addition. Rather than reversing the transcriptional upregulation of lipid metabolism-associated genes, many genes were found further upregulated by chloroquine co-treatment in livers of ERR⍺-null mice, with evidence linking the impaired management of hepatic lipid overload to underling mitochondrial dysfunction. Together, these findings underscore a critical role of ERR⍺ in reversing MASLD.

ORGANISM(S): Mus musculus

PROVIDER: GSE330751 | GEO | 2026/08/17

REPOSITORIES: GEO

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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.

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Rapamycin-induced fatty liver in mice is attenuated by chloroquine co-treatment in an ERR⍺-dependent manner

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