A single-nucleus transcriptomic atlas of primate liver aging uncovers the pro-senescence role of SREBP2 in hepatocytes.

IF 13.6 1区 生物学 Q1 CELL BIOLOGY Protein & Cell Pub Date : 2024-02-01 DOI:10.1093/procel/pwad039
Shanshan Yang, Chengyu Liu, Mengmeng Jiang, Xiaoqian Liu, Lingling Geng, Yiyuan Zhang, Shuhui Sun, Kang Wang, Jian Yin, Shuai Ma, Si Wang, Juan Carlos Izpisua Belmonte, Weiqi Zhang, Jing Qu, Guang-Hui Liu
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Abstract

Aging increases the risk of liver diseases and systemic susceptibility to aging-related diseases. However, cell type-specific changes and the underlying mechanism of liver aging in higher vertebrates remain incompletely characterized. Here, we constructed the first single-nucleus transcriptomic landscape of primate liver aging, in which we resolved cell type-specific gene expression fluctuation in hepatocytes across three liver zonations and detected aberrant cell-cell interactions between hepatocytes and niche cells. Upon in-depth dissection of this rich dataset, we identified impaired lipid metabolism and upregulation of chronic inflammation-related genes prominently associated with declined liver functions during aging. In particular, hyperactivated sterol regulatory element-binding protein (SREBP) signaling was a hallmark of the aged liver, and consequently, forced activation of SREBP2 in human primary hepatocytes recapitulated in vivo aging phenotypes, manifesting as impaired detoxification and accelerated cellular senescence. This study expands our knowledge of primate liver aging and informs the development of diagnostics and therapeutic interventions for liver aging and associated diseases.

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灵长类动物肝脏衰老的单核转录组图谱揭示了 SREBP2 在肝细胞中的促衰老作用。
衰老会增加罹患肝脏疾病的风险,并增加全身对衰老相关疾病的易感性。然而,高等脊椎动物肝脏衰老的细胞特异性变化和内在机制仍未完全阐明。在这里,我们首次构建了灵长类动物肝脏衰老的单核转录组图谱,其中我们解析了三个肝区肝细胞中细胞类型特异性基因表达的波动,并检测到肝细胞和生态位细胞之间异常的细胞-细胞相互作用。在对这一丰富的数据集进行深入分析后,我们发现脂质代谢受损和慢性炎症相关基因上调与衰老过程中肝功能下降密切相关。特别是,固醇调节元件结合蛋白(SREBP)信号的过度激活是衰老肝脏的一个特征,因此,在人类原代肝细胞中强制激活SREBP2可再现体内衰老表型,表现为解毒功能受损和细胞衰老加速。这项研究拓展了我们对灵长类动物肝脏衰老的认识,为开发肝脏衰老及相关疾病的诊断和治疗干预措施提供了信息。
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来源期刊
Protein & Cell
Protein & Cell CELL BIOLOGY-
CiteScore
24.00
自引率
0.90%
发文量
1029
审稿时长
6-12 weeks
期刊介绍: Protein & Cell is a monthly, peer-reviewed, open-access journal focusing on multidisciplinary aspects of biology and biomedicine, with a primary emphasis on protein and cell research. It publishes original research articles, reviews, and commentaries across various fields including biochemistry, biophysics, cell biology, genetics, immunology, microbiology, molecular biology, neuroscience, oncology, protein science, structural biology, and translational medicine. The journal also features content on research policies, funding trends in China, and serves as a platform for academic exchange among life science researchers.
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