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Involvement of BRD4 in alcoholic liver injury: Autophagy modulation via regulation of the SIRT1/Beclin1 axis.
Liu, Jin-Yu; Liu, Zhen-Long; Yang, Ming; Du, Chang-Lin; Zhu, Yan; Sun, Li-Jiao; Lv, Xong-Wen; Huang, Cheng; Li, Jun.
Afiliación
  • Liu JY; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
  • Liu ZL; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
  • Yang M; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
  • Du CL; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
  • Zhu Y; The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
  • Sun LJ; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China.
  • Lv XW; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China. Electronic address: lxw31288@aliyun.com.
  • Huang C; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China. Electronic address: huangcheng@ahmu.edu.cn.
  • Li J; Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China. Electronic address: lj@ahmu.edu.cn.
Lab Invest ; : 102134, 2024 Sep 20.
Article en En | MEDLINE | ID: mdl-39307311
ABSTRACT
Alcoholic liver disease (ALD) caused by chronic alcohol abuse involves complex processes from steatosis to fibrosis, cirrhosis, and hepatocellular carcinoma, posing a global health issue. Bromodomain protein 4 (BRD4) typically serves as a "reader" modulating the functions of transcription factors involved in various biological processes and disease progression. However, the specific mechanisms underlying alcoholic liver injury remain unclear. Here, we detected aberrant BRD4 expression in the alcohol-induced ALD mouse model of chronic and binge ethanol feeding developed by the National Institute on Alcohol Abuse and Alcoholism (NIAAA model), consistent with the in vitro results in Aml-12 mouse hepatocytes. Blocking and inhibiting BRD4 restored the impaired autophagic flux and lysosomal functions in alcohol-treated Aml-12 cells, whereas BRD4 overexpression reduced the expression levels of autophagy marker and lysosomal genes. Furthermore, mouse BRD4 knockdown, mediated by a short hairpin RNA carried by the adeno-associated virus serotype 8, significantly attenuated the alcohol-induced hepatocyte damage, including lipid deposition and inflammatory cell infiltration. Mechanistically, BRD4 overexpression in alcoholic liver injury inhibited the expression of sirtuin (SIRT)-1 in Aml-12 cells. Chromatin immunoprecipitation and dual-luciferase reporter assays revealed that BRD4 functions as a transcription factor and suppressor, actively binding to the SIRT1 promoter region and inhibiting its transcription. SIRT1 activated autophagy, which was suppressed in alcoholic liver injury via Beclin1 deacetylation. In conclusion, our study revealed that BRD4 negatively regulated the SIRT1/Beclin1 axis and that its deficiency alleviated alcohol-induced liver injury in mice, thus providing a new strategy for ALD treatment.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Lab Invest Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Idioma: En Revista: Lab Invest Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos