中国科学院昆明动物研究所机构知识库

钙调磷酸酶（CN）是真核生物界普遍存在的一种高度保守的蛋白磷酸酶2B（PP2B）。在CN发现后的近四十年里，其在不同生物物种上的生物学功能已得到广泛而深入的研究，尤其是作为临床上常用免疫抑制剂的生物学靶点的发现而广受关注。在本文的研究中，我们以秀丽线虫为动物模型揭示了CN一种新的生物学功能——脂肪代谢调节，并试图从遗传学及分子生物学角度阐明这一功能的潜在生物学机制。我们的研究发现：与正常野生型相比较，CN功能缺失型秀丽线虫的食物摄取速度减慢，食物摄取量减少，并且对脂肪酸等营养物质的吸收效率降低；与此同时其体内脂肪分解（尤其是与fasting相关的脂解lipophagy）速率加快，而脂肪从头合成速率水平未增加反而略微降低。这些因素改变的的导致CN功能缺失性秀丽线虫体内脂肪含量显著降低。然而，当AMPK同时缺失突变后则能不同程度恢复CN功能缺失引起的低脂肪含量，同时也能部分恢复CN功能缺失型突变株的其它表型如寿命，体长，后代数量（生殖力），咽部泵动速度等，证明AMPK与CN在生物学功能方面的相互拮抗的调节功能作用。这些研究结果提示我们CN作为代谢的关键调节因子，作用于另一个关键调节因子AMPK信号的上游或通过一个与此平行的信号通路来发挥作用。我们的研究为免疫抑制剂环孢菌素（CsA）及他克莫司（FK-506）引起脂代谢紊乱的机理做出了阐释。这些发现可能为临床上免疫治疗引起的血脂异常及胰岛素抵抗提供帮助。

Calcineurin (CN), a well conserved protein phosphatase 2B (PP2B) in eukaryotes, its biological functions have been extensively studied in different kinds of organisms in the past 40 years. Here our study uncovered the novel function of CN in lipid metabolism and the underlying mechanisms of the biological process in the nematode Caenorhabditis elegans. The deficiency of CN leads to decreased food uptake, nutrient absorption, lipogenesis and enhanced lipolysis as well. These alterations synergistically contribute to the decreased fat storage displayed in CN depleted worms. Moreover, AMPK depletion reversed all of the processes in Calcineurin mutants and then partially restored the fat storage. In addition, AMPK also antagonize with CN in other physiological aspects such as longevity, body size, fertility and pumping rates. These results implies CN as a key metabolic regulator that acts upstream of AMPK and antagonize with it. Our work provide new insights into the regulation of lipid metabolism and how CN inhibitors Cyclosporin A (CsA) and Tacrolimus (FK-506) cause lipid dysfunction. These findings may contribute to the development of dyslipidemia and insulin resistance associated with immunosuppressive therapy.