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1.
J Biol Chem ; 300(3): 105691, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38280429

RESUMO

Liver fibrosis commences with liver injury stimulating transforming growth factor beta (TGFß) activation of hepatic stellate cells (HSCs), causing scarring and irreversible damage. TGFß induces expression of the transcription factor Forkhead box S1 (FOXS1) in hepatocytes and may have a role in the pathogenesis of hepatocellular carcinoma (HCC). To date, no studies have determined how it affects HSCs. We analyzed human livers with cirrhosis, HCC, and a murine fibrosis model and found that FOXS1 expression is significantly higher in fibrotic livers but not in HCC. Next, we treated human LX2 HSC cells with TGFß to activate fibrotic pathways, and FOXS1 mRNA was significantly increased. To study TGFß-FOXS1 signaling, we developed human LX2 FOXS1 CRISPR KO and scrambled control HSCs. To determine differentially expressed gene transcripts controlled by TGFß-FOXS1, we performed RNA-seq in the FOXS1 KO and control cells and over 400 gene responses were attenuated in the FOXS1 KO HSCs with TGFß-activation. To validate the RNA-seq findings, we used our state-of-the-art PamGene PamStation kinase activity technology that measures hundreds of signaling pathways nonselectively in real time. Using our RNA-seq data, kinase activity data, and descriptive measurements, we found that FOXS1 controls pathways mediating TGFß responsiveness, protein translation, and proliferation. Our study is the first to identify that FOXS1 may serve as a biomarker for liver fibrosis and HSC activation, which may help with early detection of hepatic fibrosis or treatment options for end-stage liver disease.


Assuntos
Fatores de Transcrição Forkhead , Expressão Gênica , Células Estreladas do Fígado , Cirrose Hepática , Fator de Crescimento Transformador beta , Animais , Humanos , Camundongos , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proliferação de Células/genética , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/metabolismo , Cirrose Hepática/diagnóstico , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/farmacologia , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Biomarcadores/metabolismo , Técnicas de Inativação de Genes , Proteínas Quinases/genética , Proteínas Quinases/metabolismo , Transdução de Sinais/genética
2.
Prostaglandins Other Lipid Mediat ; 173: 106840, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38830399

RESUMO

We have previously demonstrated that the glucocorticoid receptor ß (GRß) isoform induces hepatic steatosis in mice fed a normal chow diet. The GRß isoform inhibits the glucocorticoid-binding isoform GRα, reducing responsiveness and inducing glucocorticoid resistance. We hypothesized that GRß regulates lipids that cause metabolic dysfunction. To determine the effect of GRß on hepatic lipid classes and molecular species, we overexpressed GRß (GRß-Ad) and vector (Vec-Ad) using adenovirus delivery, as we previously described. We fed the mice a normal chow diet for 5 days and harvested the livers. We utilized liquid chromatography-mass spectrometry (LC-MS) analyses of the livers to determine the lipid species driven by GRß. The most significant changes in the lipidome were monoacylglycerides and cholesterol esters. There was also increased gene expression in the GRß-Ad mice for lipogenesis, eicosanoid synthesis, and inflammatory pathways. These indicate that GRß-induced glucocorticoid resistance may drive hepatic fat accumulation, providing new therapeutic advantages.


Assuntos
Eicosanoides , Glucocorticoides , Inflamação , Lipogênese , Fígado , Receptores de Glucocorticoides , Animais , Camundongos , Fígado/metabolismo , Receptores de Glucocorticoides/metabolismo , Receptores de Glucocorticoides/genética , Eicosanoides/metabolismo , Glucocorticoides/metabolismo , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Metabolismo dos Lipídeos
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