2. Academic Validation
  3. Targeting BRD4 mitigates hepatocellular lipotoxicity by suppressing the NLRP3 inflammasome activation and GSDMD-mediated hepatocyte pyroptosis

Targeting BRD4 mitigates hepatocellular lipotoxicity by suppressing the NLRP3 inflammasome activation and GSDMD-mediated hepatocyte pyroptosis

  • Cell Mol Life Sci. 2024 Jul 9;81(1):295. doi: 10.1007/s00018-024-05328-7.
Fangyuan Chen # 1,  Shuyu Li # 1,  Min Liu 2,  Cheng Qian 3,  Zhiyin Shang 2,  Xu Song 4,  Wei Jiang 5 6,  Chuantao Tu 7
Affiliations

Affiliations

  • 1 Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
  • 2 Department of Gastroenterology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China.
  • 3 Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 4 Department of Pathology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China.
  • 5 Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China. jiang.wei@zs-hospital.sh.cn.
  • 6 Department of Gastroenterology and Hepatology, Zhongshan Hospital (Xiamen), Fudan University, Shanghai, 361015, China. jiang.wei@zs-hospital.sh.cn.
  • 7 Department of Gastroenterology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, 201508, China. tuchuantao@shaphc.org.
  • # Contributed equally.
PMID: 38977508 DOI: 10.1007/s00018-024-05328-7
Abstract

Nod-like receptor family pyrin-containing protein 3 (NLRP3) inflammasome plays a pathologic role in metabolic dysfunction-associated steatohepatitis (MASH), but the molecular mechanism regulating the NLRP3 inflammasome activation in hepatocellular lipotoxicity remains largely unknown. Bromodomain-containing protein 4 (BRD4) has emerged as a key epigenetic reader of acetylated lysine residues in enhancer regions that control the transcription of key genes. The aim of this study is to investigate if and how BRD4 regulated the NLRP3 inflammasome activation and Pyroptosis in MASH. Using the AML12 and primary mouse hepatocytes stimulated by palmitic acid (PA) as an in vitro model of hepatocellular lipotoxicity, we found that targeting BRD4 by genetic knockdown or a selective BRD4 Inhibitor MS417 protected against hepatosteatosis; and this protective effect was attributed to inhibiting the activation of NLRP3 inflammasome and reducing the expression of Caspase-1, gasdermin D (GSDMD), interleukin (IL)-1β and IL-6. Moreover, BRD4 inhibition limited the voltage-dependent anion channel-1 (VDAC1) expression and oligomerization in PA-treated AML12 hepatocytes, thereby suppressing the NLRP3 inflammasome activation. Additionally, the expression of BRD4 enhanced in MASH livers of humans. Mechanistically, BRD4 was upregulated during hepatocellular lipotoxicity that in turn modulated the active epigenetic MARK H3K27ac at the promoter regions of the VDAC and Gsdmd genes, thereby enhancing the expression of VDAC and GSDMD. Altogether, our data provide novel insights into epigenetic mechanisms underlying BRD4 activating the NLRP3 inflammasome and promoting GSDMD-mediated Pyroptosis in hepatocellular lipotoxicity. Thus, BRD4 might serve as a novel therapeutic target for the treatment of MASH.

Keywords

Cell death; Histone acetylation; IL-1β; Liver inflammation; Mitochondria.

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