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衰老相关的 13-HODE 产生通过直接抑制过氧化氢酶活性促进与年龄相关的肝脂肪变性。

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

机构信息

NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China.

Department of Physiology and Pathophysiology, Tianjin Medical University, Tianjin, China.

出版信息

Nat Commun. 2023 Dec 9;14(1):8151. doi: 10.1038/s41467-023-44026-z.

DOI:10.1038/s41467-023-44026-z
PMID:38071367
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10710422/
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.

摘要

衰老是代谢紊乱的一个主要危险因素。多不饱和脂肪酸衍生的生物活性脂质作为代谢过程中的信号分子起着关键作用。然而，它们对与年龄相关的肝脂肪变性的影响尚不清楚。在这里，我们表明衰老的肝细胞以旁分泌的方式诱导肝脂肪变性。亚油酸衍生的 9-羟基-十八碳二烯酸（9-HODE）和 13-HODE 在中年（12 个月大）和老年（20 个月大）雄性小鼠肝脏和衰老的肝细胞和巨噬细胞的条件培养基中增加。13-HODE 和 9-HODE 产生的酶花生四烯酸 15-脂氧合酶在衰老细胞中上调。9-HODE 和 13-HODE 混合物诱导肝脂肪变性并激活 SREBP1。此外，过氧化氢酶（CAT）是 13-HODE 的直接靶标，其活性被 13-HODE 降低。CAT 的过表达减少了 13-HODE 诱导的肝脂肪变性，并保护雄性小鼠免受与年龄相关的肝脂肪变性。因此，衰老的肝细胞和巨噬细胞产生的 13-HODE 通过直接抑制 CAT 活性激活 SREBP1，并促进肝脂肪变性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/b7a6c3367289/41467_2023_44026_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/096ae364308f/41467_2023_44026_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/ecacca9e6176/41467_2023_44026_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/e226356a3168/41467_2023_44026_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/a0d55530df82/41467_2023_44026_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/3928b32502bc/41467_2023_44026_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/eed2c7cd8e83/41467_2023_44026_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/4f8a9be8e312/41467_2023_44026_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/b7a6c3367289/41467_2023_44026_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/096ae364308f/41467_2023_44026_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/ecacca9e6176/41467_2023_44026_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/e226356a3168/41467_2023_44026_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/a0d55530df82/41467_2023_44026_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/3928b32502bc/41467_2023_44026_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/eed2c7cd8e83/41467_2023_44026_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/4f8a9be8e312/41467_2023_44026_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6a39/10710422/b7a6c3367289/41467_2023_44026_Fig8_HTML.jpg

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