Depletion of <i>stearoyl-CoA desaturase</i> (<i>scd</i>) leads to fatty liver disease and defective mating behavior in zebrafish
Shanshan Xu, 武汉大学基础医学院遗传学系, 湖北 武汉 430071, 中国, Yi Li, Hou-Peng Wang, Wenbo Chen, Yaqing Wang, Ziwei Song, Hui Liu, Shan Zhong, Yonghua Sun, 中国科学院水生生物研究所种子设计创新研究院淡水生态与生物技术国家重点实验室, 湖北洪山实验室, 湖北 武汉 430072, 中国, 中国科学院大学现代农业科学学院, 北京 100049, 中国, 湖北省过敏及免疫相关疾病重点实验室，湖北 武汉 430071，中国a
Abstract
Stearyl coenzyme A desaturase (SCD), also known as delta-9 desaturase, catalyzes the rate-limiting step in the formation of monounsaturated fatty acids. In mammals, depletion or inhibition of SCD activity generally leads to a decrease in triglycerides and cholesteryl esters. However, the endogenous role of <i>scd</i> in teleost fish remains unknown. Here, we generated a zebrafish <i>scd</i> mutant (<i>scd</i><sup><i>-/-</i></sup>) to elucidate the role of <i>scd</i> in lipid metabolism and sexual development. Gas chromatography-mass spectrometry (GC-MS) showed that the <i>scd</i><sup><i> <b>-/-</b> </i></sup> mutants had increased levels of saturated fatty acids C16:0 and C18:0, and decreased levels of monounsaturated fatty acids C16:1 and C18:1. The mutant fish displayed a short stature and an enlarged abdomen during development. Unlike <i>Scd</i><sup><i>-/-</i></sup> mammals, the <i>scd</i><sup><i>-/-</i></sup> zebrafish showed significantly increased fat accumulation in the whole body, especially in the liver, leading to hepatic mitochondrial dysfunction and severe cell apoptosis. Mechanistically, <i>srebf1</i>, a gene encoding a transcriptional activator related to adipogenesis, <i>acc1</i> and <i>acaca</i>, genes involved in fatty acid synthesis, and <i>dgat2</i>, a key gene involved in triglyceride synthesis, were significantly upregulated in mutant livers to activate fatty acid biosynthesis and adipogenesis. The <i>scd</i><sup><i>-/-</i></sup> males exhibited defective natural mating behavior due to defective genital papillae but possessed functional mature sperm. All defects in the<i> scd</i><sup><i>-/-</i></sup> mutants could be rescued by ubiquitous transgenic overexpression of <i>scd</i>. In conclusion, our study demonstrates that <i>scd</i> is indispensable for maintaining lipid homeostasis and development of secondary sexual characteristics in zebrafish.