Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, 01307, Germany.
Department of Physiology, Faculty of Medicine, Technische Universität Dresden, Dresden, 01307, Germany.
Sci Adv. 2023 Jul 21;9(29):eadf6710. doi: 10.1126/sciadv.adf6710.
Corticosteroids regulate vital processes, including stress responses, systemic metabolism, and blood pressure. Here, we show that corticosteroid synthesis is related to the polyunsaturated fatty acid (PUFA) content of mitochondrial phospholipids in adrenocortical cells. Inhibition of the rate-limiting enzyme of PUFA synthesis, fatty acid desaturase 2 (FADS2), leads to perturbations in the mitochondrial lipidome and diminishes steroidogenesis. Consistently, the adrenocortical mitochondria of mice fed a diet with low PUFA concentration are structurally impaired and corticoid levels are decreased. On the contrary, FADS2 expression is elevated in the adrenal cortex of obese mice, and plasma corticosterone is increased, which can be counteracted by dietary supplementation with the FADS2 inhibitor SC-26192 or icosapent ethyl, an eicosapentaenoic acid ethyl ester. In humans, expression is elevated in aldosterone-producing adenomas compared to non-active adenomas or nontumorous adrenocortical tissue and correlates with expression of steroidogenic genes. Our data demonstrate that FADS2-mediated PUFA synthesis determines adrenocortical steroidogenesis in health and disease.
皮质甾类调节重要的生理过程，包括应激反应、全身代谢和血压。在这里，我们发现皮质甾类合成与肾上腺皮质细胞线粒体磷脂中的多不饱和脂肪酸（PUFA）含量有关。抑制多不饱和脂肪酸合成的限速酶，脂肪酸去饱和酶 2（FADS2），会导致线粒体脂类组发生紊乱，并减少类固醇的生成。一致的是，用低 PUFA 浓度饮食喂养的 小鼠的肾上腺皮质线粒体结构受损，皮质激素水平降低。相反，肥胖小鼠的肾上腺皮质中 FADS2 的表达增加，血浆皮质酮增加，而用 FADS2 抑制剂 SC-26192 或二十碳五烯酸乙酯（icosapent ethyl）饮食补充可以抵消这种增加。在人类中，与非活性腺瘤或非肿瘤性肾上腺皮质组织相比，醛固酮产生性腺瘤中 的表达升高，并且与类固醇生成基因的表达相关。我们的数据表明，FADS2 介导的多不饱和脂肪酸合成决定了健康和疾病中的肾上腺皮质类固醇生成。
