Nasiri Maryam, Nikolaou Nikolaos, Parajes Silvia, Krone Nils P, Valsamakis George, Mastorakos George, Hughes Beverly, Taylor Angela, Bujalska Iwona J, Gathercole Laura L, Tomlinson Jeremy W
Centre for Endocrinology, Diabetes and Metabolism (M.N., S.P., N.P.K., B.H., A.T., I.J.B.), Institute of Biomedical Research, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom; Oxford Centre for Diabetes, Endocrinology & Metabolism (N.N., L.L.G., J.W.T.), NIHR Oxford Biomedical Research Centre, University of Oxford, Churchill Hospital, Headington, Oxford OX3 7LJ, United Kingdom; and Endocrine Unit, Second Department of Obstetrics and Gynecology and Pathology Department (G.V., G.M.), Aretaieion University Hospital, Athens Medical School, Athens, 11528, Greece.
Endocrinology. 2015 Aug;156(8):2863-71. doi: 10.1210/en.2015-1149. Epub 2015 May 14.
Glucocorticoids and androgens have both been implicated in the pathogenesis of nonalcoholic fatty liver disease (NAFLD); androgen deficiency in males, androgen excess in females, and glucocorticoid excess in both sexes are associated with NAFLD. Glucocorticoid and androgen action are regulated at a prereceptor level by the enzyme 5α-reductase type 2 (SRD5A2), which inactivates glucocorticoids to their dihydrometabolites and converts T to DHT. We have therefore explored the role of androgens and glucocorticoids and their metabolism by SRD5A2 upon lipid homeostasis in human hepatocytes. In both primary human hepatocytes and human hepatoma cell lines, glucocorticoids decreased de novo lipogenesis in a dose-dependent manner. Whereas androgen treatment (T and DHT) increased lipogenesis in cell lines and in primary cultures of human hepatocytes from female donors, it was without effect in primary hepatocyte cultures from men. SRD5A2 overexpression reduced the effects of cortisol to suppress lipogenesis and this effect was lost following transfection with an inactive mutant construct. Conversely, pharmacological inhibition using the 5α-reductase inhibitors finasteride and dutasteride augmented cortisol action. We have demonstrated that manipulation of SRD5A2 activity can regulate lipogenesis in human hepatocytes in vitro. This may have significant clinical implications for those patients prescribed 5α-reductase inhibitors, in particular augmenting the actions of glucocorticoids to modulate hepatic lipid flux.
糖皮质激素和雄激素均与非酒精性脂肪性肝病（NAFLD）的发病机制有关；男性雄激素缺乏、女性雄激素过多以及男女两性糖皮质激素过多均与NAFLD相关。糖皮质激素和雄激素的作用在受体前水平由2型5α-还原酶（SRD5A2）调节，该酶将糖皮质激素转化为其二氢代谢产物并将睾酮（T）转化为双氢睾酮（DHT）。因此，我们探讨了雄激素和糖皮质激素及其通过SRD5A2代谢对人肝细胞脂质稳态的作用。在原代人肝细胞和人肝癌细胞系中，糖皮质激素均以剂量依赖的方式降低从头脂肪生成。雄激素处理（T和DHT）增加了细胞系和来自女性供体的人肝细胞原代培养物中的脂肪生成，但对来自男性的原代肝细胞培养物没有影响。SRD5A2的过表达降低了皮质醇抑制脂肪生成的作用，在用无活性突变体构建体转染后这种作用消失。相反，使用5α-还原酶抑制剂非那雄胺和度他雄胺的药理学抑制增强了皮质醇的作用。我们已经证明，在体外操纵SRD5A2的活性可以调节人肝细胞中的脂肪生成。这对于那些服用5α-还原酶抑制剂的患者可能具有重要的临床意义，特别是增强糖皮质激素调节肝脏脂质通量的作用。
