Senescence-associated 13-HODE production promotes age-related liver steatosis by directly inhibiting catalase activity

Jinjie Duan, Wenhui Dong, Guangyan Wang, Wenjing Xiu, Guangyin Pu, Jingwen Xu, Chenji Ye, Xu Zhang (), Yi Zhu () and Chunjiong Wang ()
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Jinjie Duan: Tianjin Medical University
Wenhui Dong: Tianjin Medical University
Guangyan Wang: Tianjin Medical University
Wenjing Xiu: Tianjin Medical University
Guangyin Pu: Tianjin Medical University
Jingwen Xu: Tianjin Medical University
Chenji Ye: Xinxiang Medical University
Xu Zhang: Tianjin Medical University
Yi Zhu: Tianjin Medical University
Chunjiong Wang: Tianjin Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: Abstract Aging is a major risk factor for metabolic disorders. Polyunsaturated fatty acid-derived bioactive lipids play critical roles as signaling molecules in metabolic processes. Nonetheless, their effects on age-related liver steatosis remain unknown. Here we show that senescent liver cells induce liver steatosis in a paracrine manner. Linoleic acid-derived 9-hydroxy-octadecadienoic acid (9-HODE) and 13-HODE increase in middle-aged (12-month-old) and aged (20-month-old) male mouse livers and conditioned medium from senescent hepatocytes and macrophages. Arachidonate 15-lipoxygenase, an enzyme for 13-HODE and 9-HODE production, is upregulated in senescent cells. A 9-HODE and 13-HODE mixture induces liver steatosis and activates SREBP1. Furthermore, catalase (CAT) is a direct target of 13-HODE, and its activity is decreased by 13-HODE. CAT overexpression reduces 13-HODE-induced liver steatosis and protects male mice against age-related liver steatosis. Therefore, 13-HODE produced by senescent hepatocytes and macrophages activates SREBP1 by directly inhibiting CAT activity and promotes liver steatosis.

Date: 2023
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DOI: 10.1038/s41467-023-44026-z

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