Oka Shintaro, Shiraishi Koji, Fujimoto Mitsuaki, Katiyar Arpit, Takii Ryosuke, Nakai Akira, Matsuyama Hideyasu
Department of Urology, School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8505, Japan.
Department of Biochemistry and Molecular Biology, School of Medicine, Yamaguchi University, Ube, Yamaguchi 755-8505, Japan.
Endocrinology. 2017 Aug 1;158(8):2648-2658. doi: 10.1210/en.2017-00132.
Testicular testosterone synthesis begins with cholesterol transport into mitochondria via steroidogenic acute regulatory (StAR) protein in Leydig cells. Acute heat stress is known to obstruct testicular steroidogenesis by transcriptional repression of StAR. In contrast, chronic heat stress such as cryptorchidism or varicocele generally does not affect testicular steroidogenesis, suggesting that Leydig cells adapt to heat stress and retain their steroid synthesis ability. However, the mechanisms of the stress response in steroid-producing cells are unclear. We examined the relationship between the heat stress response and heat shock factor 1 (HSF1), which protects cells from proteotoxic stress by inducing heat shock protein as a molecular chaperone. The influences of HSF1 deficiency on cholesterol transport by StAR and the expression of steroidogenic enzymes under chronic heat stress were studied in testes of HSF1-knockout (HSF1KO) mice with experimental cryptorchidism. StAR protein in wild-type-cryptorchid mice was transiently decreased after induction of cryptorchidism and then gradually returned to basal levels. In contrast, StAR protein in HSF1KO mice continued to decrease and failed to recover, resulting in impaired serum testosterone. StAR messenger RNA was not decreased with cryptorchidism, indicating that posttranslational modification of StAR, not its transcription, was obstructed in cryptorchidism. Other steroidogenic enzymes, including CYP11A1, 3β-HSD, and CYP17A1, were not decreased. Lipid droplets were increased in the cytosol of HSF1KO-cryptorchid mice, suggesting dysfunctional cholesterol transportation. These findings provide insight into the role of HSF1 in Leydig cell steroidogenesis, suggesting that it maintains cholesterol transport by recovering StAR under chronic heat stress.
睾丸睾酮合成始于胆固醇通过睾丸间质细胞中的类固醇生成急性调节（StAR）蛋白转运至线粒体。已知急性热应激通过对StAR的转录抑制来阻碍睾丸类固醇生成。相比之下，诸如隐睾症或精索静脉曲张等慢性热应激通常不影响睾丸类固醇生成，这表明睾丸间质细胞适应热应激并保留其类固醇合成能力。然而，类固醇生成细胞中应激反应的机制尚不清楚。我们研究了热应激反应与热休克因子1（HSF1）之间的关系，HSF1作为分子伴侣通过诱导热休克蛋白来保护细胞免受蛋白毒性应激。在患有实验性隐睾症的HSF1基因敲除（HSF1KO）小鼠的睾丸中，研究了HSF1缺乏对慢性热应激下StAR介导的胆固醇转运以及类固醇生成酶表达的影响。野生型隐睾小鼠中的StAR蛋白在隐睾症诱导后短暂减少，然后逐渐恢复至基础水平。相比之下，HSF1KO小鼠中的StAR蛋白持续减少且未能恢复，导致血清睾酮受损。隐睾症并未使StAR信使核糖核酸减少，这表明在隐睾症中StAR的翻译后修饰而非转录受到阻碍。包括CYP11A1、3β - HSD和CYP17A1在内的其他类固醇生成酶并未减少。HSF1KO - 隐睾小鼠的细胞质中脂滴增加，提示胆固醇转运功能失调。这些发现为HSF1在睾丸间质细胞类固醇生成中的作用提供了见解，表明它在慢性热应激下通过恢复StAR来维持胆固醇转运。
