TSH-stimulated hepatocyte exosomes modulate liver-adipose triglyceride accumulation via the TGF-β1/ATGL axis in mice.

IF 3.9 2区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

Lipids in Health and Disease Pub Date : 2025-03-06 DOI:10.1186/s12944-025-02509-6

Shizhan Ma, Yayun Wang, Shuteng Fan, Wanli Jiang, Mingliang Sun, Mengzhe Jing, Wenkai Bi, Meng Zhou, Dongming Wu

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引用次数: 0

Abstract

Subclinical hypothyroidism (SCH) contributes to obesity, with the liver acting as a crucial metabolic regulator. Thyroid-stimulating hormone (TSH) affects systemic lipid balance, potentially linking SCH to obesity. While the direct impact of TSH on hepatic lipid metabolism has been extensively documented, its role in modulating lipid dynamics in peripheral organs through liver-mediated pathways remains insufficiently understood. This study identifies TSH-stimulated hepatocyte-derived exosomes (exosomes^TSH) as key mediators in liver-adipose communication, promoting triglyceride accumulation in adipocytes via the transforming growth factor-beta 1 (TGF-β1)/adipose triglyceride lipase (ATGL) axis. Exosomes^TSH enhance lipid storage in adipocytes, significantly increasing triglyceride content and lipid droplet formation while reducing lipolysis, effects that are dependent on TSH receptor (TSHR) activation in hepatocytes. In vivo, exosomes^TSH induce weight gain and adipose tissue expansion, impairing glucose metabolism in both chow- and high-fat diet-fed mice. Mechanistically, exosomes^TSH upregulate TGF-β1 and downregulate ATGL in adipocytes, establishing the TGF-β1/ATGL pathway as essential for exosome-mediated lipid accumulation. Further, miR-139-5p is identified as a modulator of TGF-β1 expression within this pathway, with overexpression of miR-139-5p alleviating exosomes^TSH-induced lipid accumulation in adipocytes. This study elucidates a novel miR-139-5p-dependent mechanism through which TSH modulates lipid metabolism via liver-derived exosomes, highlighting the pivotal role of miR-139-5p in linking SCH to adipose lipid accumulation through the TGF-β1/ATGL signaling axis.

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来源期刊

Lipids in Health and Disease 生物-生化与分子生物学

CiteScore

7.70

自引率

2.20%

发文量

122

审稿时长

3-8 weeks

期刊介绍： Lipids in Health and Disease is an open access, peer-reviewed, journal that publishes articles on all aspects of lipids: their biochemistry, pharmacology, toxicology, role in health and disease, and the synthesis of new lipid compounds. Lipids in Health and Disease is aimed at all scientists, health professionals and physicians interested in the area of lipids. Lipids are defined here in their broadest sense, to include: cholesterol, essential fatty acids, saturated fatty acids, phospholipids, inositol lipids, second messenger lipids, enzymes and synthetic machinery that is involved in the metabolism of various lipids in the cells and tissues, and also various aspects of lipid transport, etc. In addition, the journal also publishes research that investigates and defines the role of lipids in various physiological processes, pathology and disease. In particular, the journal aims to bridge the gap between the bench and the clinic by publishing articles that are particularly relevant to human diseases and the role of lipids in the management of various diseases.