Targeting the chromatin remodeler BAZ2B mitigates hepatic senescence and MASH fibrosis.

IF 17 Q1 CELL BIOLOGY
Nature aging Pub Date : 2025-06-01 Epub Date: 2025-05-19 DOI:10.1038/s43587-025-00862-w
Chuantao Tu, Cheng Qian, Shuyu Li, De-Ying Lin, Zhi-Yang Liu, Wan-Gan Ouyang, Xin-Lei Kang, Fangyuan Chen, Shu Song, Shi-Qing Cai
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Abstract

With increased age, the liver becomes more vulnerable to metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis. Deciphering the complex interplay between aging, the emergence of senescent cells in the liver and MASH fibrosis is critical for developing treatments. Here we report an epigenetic mechanism that links liver aging to MASH fibrosis. We find that upregulation of the chromatin remodeler BAZ2B in a subpopulation of hepatocytes (HEPs) is linked to MASH pathology in patients. Genetic ablation or hepatocyte-specific knockdown of Baz2b in mice attenuates HEP senescence and MASH fibrosis by preserving peroxisome proliferator-activated receptor α (PPARα)-mediated lipid metabolism, which was impaired in both naturally aged and MASH mouse livers. Mechanistically, Baz2b downregulates the expression of genes related to the PPARα signaling pathway by directly binding their promoter regions and reducing chromatin accessibility. Thus, our study unravels the BAZ2B-PPARα-lipid metabolism axis as a link from liver aging to MASH fibrosis, suggesting that BAZ2B is a potential therapeutic target for HEP senescence and fibrosis.

靶向染色质重塑者BAZ2B减轻肝衰老和MASH纤维化。
随着年龄的增长,肝脏变得更容易发生代谢功能障碍相关的脂肪性肝炎(MASH)伴纤维化。破解衰老、肝脏中衰老细胞的出现和MASH纤维化之间复杂的相互作用对于开发治疗方法至关重要。在这里,我们报告了一种将肝脏衰老与MASH纤维化联系起来的表观遗传机制。我们发现肝细胞(HEPs)亚群中染色质重塑物BAZ2B的上调与患者的MASH病理有关。基因消融或小鼠肝细胞特异性敲低Baz2b通过保留过氧化物酶体增殖激活受体α (PPARα)介导的脂质代谢来减轻HEP衰老和MASH纤维化,这在自然衰老和MASH小鼠肝脏中都是受损的。从机制上讲,Baz2b通过直接结合PPARα信号通路的启动子区域和降低染色质可及性来下调PPARα信号通路相关基因的表达。因此,我们的研究揭示了BAZ2B- ppar α-脂质代谢轴从肝脏衰老到MASH纤维化的联系,表明BAZ2B是HEP衰老和纤维化的潜在治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
14.70
自引率
0.00%
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