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Impaired SUMOylation of FoxA1 promotes nonalcoholic fatty liver disease through down-regulation of Sirt6.
Zou, Dongmei; Liao, Jinwen; Xiao, Min; Liu, Liang; Dai, Dongling; Xu, Mingguo.
Afiliación
  • Zou D; The Department of Pediatric, Shenzhen Children's Hospital, China Medical University, Shenzhen, 518038, Guangdong Province, China.
  • Liao J; The Department of Pediatric, Longgang District Maternity & Child Healthcare Hospital of Shenzhen City, (Longgang Maternity and Child Institute of Shantou University Medical College), Shenzhen, 518172, Guangdong Province, China.
  • Xiao M; The Department of Pediatric, Shenzhen Children's Hospital, China Medical University, Shenzhen, 518038, Guangdong Province, China.
  • Liu L; The Department of Pediatric, Shenzhen Children's Hospital, China Medical University, Shenzhen, 518038, Guangdong Province, China.
  • Dai D; The Department of Pediatric, Shenzhen Children's Hospital, China Medical University, Shenzhen, 518038, Guangdong Province, China.
  • Xu M; The Department of Pediatric, Shenzhen Children's Hospital, China Medical University, Shenzhen, 518038, Guangdong Province, China. 18938690175@163.com.
Cell Death Dis ; 15(9): 674, 2024 Sep 14.
Article en En | MEDLINE | ID: mdl-39277582
ABSTRACT
Abnormal SUMOylation is implicated in non-alcoholic fatty liver disease (NAFLD) progression. Forkhead box protein A1 (FoxA1) has been shown to protect liver from steatosis, which was down-regulated in NAFLD. This study elucidated the role of FoxA1 deSUMOylation in NAFLD. NAFLD models were established in high-fat diet (HFD)-induced mice and palmitate acid (PAL)-treated hepatocytes. Hepatic steatosis was evaluated by biochemical and histological methods. Lipid droplet formation was determined by BODIPY and Oil red O staining. Target molecule levels were analyzed by RT-qPCR, Western blotting, and immunohistochemistry staining. SUMOylation of FoxA1 was determined by Ni-NTA pull-down assay and SUMOylation assay Ultra Kit. Protein interaction and ubiquitination were detected by Co-IP. Gene transcription was assessed by ChIP and dual luciferase reporter assays. Liver FoxA1 knockout mice developed severe liver steatosis, which could be ameliorated by sirtuin 6 (Sirt6) overexpression. Nutritional stresses reduced Sumo2/3-mediated FoxA1 SUMOylation at lysine residue K6, which promoted lipid droplet formation by repressing fatty acid ß-oxidation. Moreover, Sirt6 was a target gene of FoxA1, and Sirt6 transcription activity was restrained by deSUMOylation of FoxA1 at site K6. Furthermore, nutritional stresses-induced deSUMOylation of FoxA1 promoted the ubiquitination and degradation of FoxA1 with assistance of murine double minute 2 (Mdm2). Finally, activating FoxA1 SUMOylation delayed the progression of NAFLD in mice. DeSUMOylation of FoxA1 at K6 promotes FoxA1 degradation and then inhibits Sirt6 transcription, thereby suppressing fatty acid ß-oxidation and facilitating NAFLD development. Our findings suggest that FoxA1 SUMOylation activation might be a promising therapeutic strategy for NAFLD.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación hacia Abajo / Ratones Noqueados / Sirtuinas / Factor Nuclear 3-alfa del Hepatocito / Sumoilación / Enfermedad del Hígado Graso no Alcohólico Límite: Animals / Humans / Male Idioma: En Revista: Cell Death Dis Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Regulación hacia Abajo / Ratones Noqueados / Sirtuinas / Factor Nuclear 3-alfa del Hepatocito / Sumoilación / Enfermedad del Hígado Graso no Alcohólico Límite: Animals / Humans / Male Idioma: En Revista: Cell Death Dis Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Reino Unido