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Clin Transl Sci ; 17(6): e13760, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38847320

RESUMO

Metabolic dysfunction-associated steatohepatitis (MASH) is the severe form of non-alcoholic fatty liver disease which has a high potential to progress to cirrhosis and hepatocellular carcinoma, yet adequate effective therapies are lacking. Hypoadiponectinemia is causally involved in the pathogenesis of MASH. This study investigated the pharmacological effects of adiponectin replacement therapy with the adiponectin-derived peptide ALY688 (ALY688-SR) in a mouse model of MASH. Human induced pluripotent stem (iPS) cell-derived hepatocytes were used to test cytotoxicity and signaling of unmodified ALY688 in vitro. High-fat diet with low methionine and no added choline (CDAHF) was used to induce MASH and test the effects of ALY688-SR in vivo. Histological MASH activity score (NAS) and fibrosis score were determined to assess the effect of ALY688-SR. Transcriptional characterization of mice through RNA sequencing was performed to indicate potential molecular mechanisms involved. In cultured hepatocytes, ALY688 efficiently induced adiponectin-like signaling, including the AMP-activated protein kinase and p38 mitogen-activated protein kinase pathways, and did not elicit cytotoxicity. Administration of ALY688-SR in mice did not influence body weight but significantly ameliorated CDAHF-induced hepatic steatosis, inflammation, and fibrosis, therefore effectively preventing the development and progression of MASH. Mechanistically, ALY688-SR treatment markedly induced hepatic expression of genes involved in fatty acid oxidation, whereas it significantly suppressed the expression of pro-inflammatory and pro-fibrotic genes as demonstrated by transcriptomic analysis. ALY688-SR may represent an effective approach in MASH treatment. Its mode of action involves inhibition of hepatic steatosis, inflammation, and fibrosis, possibly via canonical adiponectin-mediated signaling.


Assuntos
Adiponectina , Modelos Animais de Doenças , Hepatócitos , Hepatopatia Gordurosa não Alcoólica , Animais , Adiponectina/metabolismo , Adiponectina/farmacologia , Adiponectina/deficiência , Camundongos , Humanos , Hepatócitos/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/patologia , Hepatopatia Gordurosa não Alcoólica/etiologia , Masculino , Camundongos Endogâmicos C57BL , Transdução de Sinais/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Erros Inatos do Metabolismo/metabolismo , Erros Inatos do Metabolismo/tratamento farmacológico , Erros Inatos do Metabolismo/patologia , Doenças Metabólicas/tratamento farmacológico , Doenças Metabólicas/metabolismo , Doenças Metabólicas/prevenção & controle , Doenças Metabólicas/etiologia , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Fígado Gorduroso/prevenção & controle , Fígado Gorduroso/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/patologia
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