Genome‐Wide Profiling of H3K27ac Identifies TDO2 as a Pivotal Therapeutic Target in Metabolic Associated Steatohepatitis Liver Disease
Abstract: H3K27ac has been widely recognized as a representative epigenetic marker of active enhancer, while its regulatory mechanisms in pathogenesis of metabolic dysfunction‐associated steatotic liver disease (MASLD) remain elusive. Here, a genome‐wide comparative study on H3K27ac activities and transcriptome profiling in high fat diet (HFD)‐induced MASLD model is performed. A significantly enhanced H3K27ac density with abundant alterations of regulatory transcriptome is observed in MASLD rats. Based on integrative analysis of ChIP‐Seq and RNA‐Seq, TDO2 is identified as a critical contributor for abnormal lipid accumulation, transcriptionally activated by YY1‐promoted H3K27ac. Furthermore, TDO2 depletion effectively protects against hepatic steatosis. In terms of mechanisms, TDO2 activates NF‐κB pathway to promote macrophages M1 polarization, representing a crucial event in MASLD progression. A bovine serum albumin nanoparticle is fabricated to provide sustained release of Allopurinol (NPs‐Allo) for TDO2 inhibition, possessing excellent biocompatibility and desired targeting capacity. Venous injection of NPs‐Allo robustly alleviates HFD‐induced metabolic disorders. This study reveals the pivotal role of TDO2 and its underlying mechanisms in pathogenesis of MASLD epigenetically and genetically. Targeting H3K27ac‐TDO2‐NF‐κB axis may provide new insights into the pathogenesis of abnormal lipid accumulation and pave the way for developing novel strategies for MASLD prevention and treatment.
- Standort
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Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
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Online-Ressource
- Sprache
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Englisch
- Erschienen in
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Genome‐Wide Profiling of H3K27ac Identifies TDO2 as a Pivotal Therapeutic Target in Metabolic Associated Steatohepatitis Liver Disease ; day:04 ; month:10 ; year:2024 ; extent:20
Advanced science ; (04.10.2024) (gesamt 20)
- Urheber
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Zhu, Yaling
Shang, Limeng
Tang, Yunshu
Li, Qiushuang
Ding, Lin
Wang, Yi
Zhang, Tiantian
Xie, Bin
Ma, Jinhu
Li, Xinyu
Chen, Shuwen
Yi, Xinrui
Peng, Jin
Liang, Youfeng
He, Anyuan
Yan, Hong
Zhu, Huaqing
Zhang, Buchun
Zhu, Yong
- DOI
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10.1002/advs.202404224
- URN
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urn:nbn:de:101:1-2410041432582.710129860762
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
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15.08.2025, 07:28 MESZ
Datenpartner
Deutsche Nationalbibliothek. Bei Fragen zum Objekt wenden Sie sich bitte an den Datenpartner.
Beteiligte
- Zhu, Yaling
- Shang, Limeng
- Tang, Yunshu
- Li, Qiushuang
- Ding, Lin
- Wang, Yi
- Zhang, Tiantian
- Xie, Bin
- Ma, Jinhu
- Li, Xinyu
- Chen, Shuwen
- Yi, Xinrui
- Peng, Jin
- Liang, Youfeng
- He, Anyuan
- Yan, Hong
- Zhu, Huaqing
- Zhang, Buchun
- Zhu, Yong
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