Department of Histology and Embryology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
Department of Histology and Embryology, School of Basic Medical Sciences, Anhui Medical University, Hefei, China.
J Lipid Res. 2024 Oct;65(10):100639. doi: 10.1016/j.jlr.2024.100639. Epub 2024 Sep 3.
Male obesity is a pandemic health issue and can disrupt testicular steroidogenesis. Here, we explored the mechanism by which a high-fat diet (HFD) induced steroidogenic inhibition. As expected, HFD induced lipid droplet accumulation and reduced the expression of StAR, P450scc, and 3β-HSD, three steroidogenic enzymes, in mouse testes. Palmitic acid (PA), a saturated fatty acid usually used to trigger lipotoxicity in vitro, induced greater accumulation of lipid droplets and the downregulation of steroidogenic enzymes in TM3 cells. Mechanistically, both HFD and PA disturbed mitochondrial fusion/fission dynamics and then induced mitochondrial dysfunction and mitophagy inhibition in mouse Leydig cells. Additionally, mitochondrial fusion promoter M1 attenuated PA-induced imbalance of mitochondrial dynamics, mitophagy inhibition, mitochondrial reactive oxygen species (ROS) production, and mitochondrial dysfunction in TM3 cells. Mitofusin 2 (Mfn2) knock-down further aggravated the PA-induced imbalance of mitochondrial dynamics, mitochondrial ROS production, and mitochondrial dysfunction in TM3 cells. Importantly, M1 rescued PA-induced downregulation of steroidogenic enzymes, whereas Mfn2 knock-down further aggravated PA-induced downregulation of steroidogenic enzymes in TM3 cells. Overall, our results provide laboratory evidence that mitochondrial dysfunction and mitophagy inhibition caused by dysregulation of mitochondrial fusion may be involved in HFD-induced steroidogenesis inhibition in mouse Leydig cells.
男性肥胖是一种全球性的健康问题，可能会干扰睾丸类固醇生成。在这里，我们探讨了高脂肪饮食（HFD）诱导类固醇生成抑制的机制。正如预期的那样，HFD 诱导脂滴积累，并降低了小鼠睾丸中 StAR、P450scc 和 3β-HSD 这三种类固醇生成酶的表达。棕榈酸（PA）是一种饱和脂肪酸，通常用于在体外引发脂毒性，它在 TM3 细胞中诱导更多的脂滴积累和类固醇生成酶的下调。在机制上，HFD 和 PA 都干扰了线粒体融合/裂变动力学，然后诱导了小鼠睾丸间质细胞中的线粒体功能障碍和自噬抑制。此外，线粒体融合促进剂 M1 减轻了 PA 诱导的线粒体动力学失衡、自噬抑制、线粒体活性氧（ROS）产生和 TM3 细胞中的线粒体功能障碍。线粒体融合蛋白 2（Mfn2）敲低进一步加重了 PA 诱导的 TM3 细胞中线粒体动力学失衡、线粒体 ROS 产生和线粒体功能障碍。重要的是，M1 挽救了 PA 诱导的类固醇生成酶下调，而 Mfn2 敲低进一步加重了 PA 诱导的 TM3 细胞中类固醇生成酶的下调。总的来说，我们的研究结果提供了实验室证据，表明线粒体融合失调引起的线粒体功能障碍和自噬抑制可能参与了 HFD 诱导的小鼠睾丸间质细胞类固醇生成抑制。
