Wang Yanli, Xie Cangsang, Diao Zhiqing, Liang Bin
Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China.
Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming 650204, China.
Molecules. 2017 Jun 26;22(7):1062. doi: 10.3390/molecules22071062.
Calcineurin is a calcium- and calmodulin-dependent serine/threonine protein phosphatase, and the target of immunosuppressive agent tacrolimus (TAC). The dysfunction of calcineurin, or clinical applications of tacrolimus, have been reported to be associated with dyslipidemia. The underlying mechanisms of calcineurin and tacrolimus in lipid metabolism are largely unknown. Here, we showed that mutations of and , which respectively encode the catalytic subunit and the regulatory subunit of calcineurin, together with tacrolimus treatment, consistently led to decreased fat accumulation and delayed growth in the nematode . In contrast, disruption of the AMP-activated protein kinase (AMPK) encoded by and reversed the above effects in worms. Moreover, calcineurin deficiency and tacrolimus treatment consistently activated the transcriptional expression of the lipolytic gene , encoding triglyceride lipase. Furthermore, RNAi knockdown of recovered the decreased fat accumulation in both calcineurin deficient and tacrolimus treated worms. Collectively, our results reveal that immunosuppressive agent tacrolimus and their target calcineurin may antagonize AMPK to regulate ATGL and lipolysis, thereby providing potential therapy for the application of immunosuppressive agents.
钙调神经磷酸酶是一种钙和钙调蛋白依赖性丝氨酸/苏氨酸蛋白磷酸酶，也是免疫抑制剂他克莫司（TAC）的作用靶点。据报道，钙调神经磷酸酶功能障碍或他克莫司的临床应用与血脂异常有关。钙调神经磷酸酶和他克莫司在脂质代谢中的潜在机制在很大程度上尚不清楚。在此，我们表明，分别编码钙调神经磷酸酶催化亚基和调节亚基的基因发生突变，再加上他克莫司处理，一致导致线虫脂肪积累减少和生长延迟。相反，由基因编码的AMP激活蛋白激酶（AMPK）的破坏逆转了蠕虫中的上述效应。此外，钙调神经磷酸酶缺乏和他克莫司处理一致激活了编码甘油三酯脂肪酶的脂解基因的转录表达。此外，RNA干扰敲低该基因可恢复钙调神经磷酸酶缺陷型和他克莫司处理型蠕虫中减少的脂肪积累。总的来说，我们的结果表明，免疫抑制剂他克莫司及其靶点钙调神经磷酸酶可能拮抗AMPK以调节脂肪甘油三酯脂肪酶（ATGL）和脂解作用，从而为免疫抑制剂的应用提供潜在治疗方法。
