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徐杉杉, 李依, 王厚鹏, 陈文博, 王亚青, 宋紫薇, 刘慧, 钟山, 孙永华. 2023: 硬脂酰辅酶A去饱和酶(scd)突变导致斑马鱼脂肪肝和交配行为缺陷. 动物学研究, 44(1): 63-77. DOI: 10.24272/j.issn.2095-8137.2022.167
引用本文: 徐杉杉, 李依, 王厚鹏, 陈文博, 王亚青, 宋紫薇, 刘慧, 钟山, 孙永华. 2023: 硬脂酰辅酶A去饱和酶(scd)突变导致斑马鱼脂肪肝和交配行为缺陷. 动物学研究, 44(1): 63-77. DOI: 10.24272/j.issn.2095-8137.2022.167
Shan-Shan Xu, Yi Li, Hou-Peng Wang, Wen-Bo Chen, Ya-Qing Wang, Zi-Wei Song, Hui Liu, Shan Zhong, Yong-Hua Sun. 2023: Depletion of stearoyl-CoA desaturase (scd) leads to fatty liver disease and defective mating behavior in zebrafish. Zoological Research, 44(1): 63-77. DOI: 10.24272/j.issn.2095-8137.2022.167
Citation: Shan-Shan Xu, Yi Li, Hou-Peng Wang, Wen-Bo Chen, Ya-Qing Wang, Zi-Wei Song, Hui Liu, Shan Zhong, Yong-Hua Sun. 2023: Depletion of stearoyl-CoA desaturase (scd) leads to fatty liver disease and defective mating behavior in zebrafish. Zoological Research, 44(1): 63-77. DOI: 10.24272/j.issn.2095-8137.2022.167

硬脂酰辅酶A去饱和酶(scd)突变导致斑马鱼脂肪肝和交配行为缺陷

Depletion of stearoyl-CoA desaturase (scd) leads to fatty liver disease and defective mating behavior in zebrafish

  • 摘要: 肝脏作为生物有机体最重要的代谢器官之一,其脂质稳态对于维持正常的生命活动具有重要作用。硬脂酰辅酶A去饱和酶 (Scd),也称为Δ9去饱和酶,是催化合成单不饱和脂肪酸合成的限速酶,在脂肪合成中具有重要作用。在哺乳动物中,Scd活性的丧失或抑制通常会导致甘油三酯和胆固醇酯合成的减少和个体脂肪囤积降低。然而,作为重要的动物蛋白来源,在鱼类中scd是如何调控脂质代谢仍然未知,同时scd在性别发育中的作用也不清楚。该研究通过CRISPR/Cas9方法成功构建了scd斑马鱼突变体模型,揭示了scd在鱼类脂质代谢和性别发育中的作用。GC-MS分析表明,scd-/- 突变体中饱和脂肪酸C16:0和C18:0水平显著升高,而单不饱和脂肪酸C16:1和C18:1水平显著降低。与Scd-/- 哺乳动物不同,scd-/-突变斑马鱼成鱼表现为躯体短小和腹部增大,其躯体尤其是肝脏中的脂肪积累显著增加,最终导致肝细胞线粒体功能障碍和严重的细胞凋亡。RNA-seq和实验生物学研究表明,脂肪酸生物合成和甘油三酯合成路径在突变体肝脏中显著上调,从而激活了脂肪酸的生物合成和脂肪生成,最终导致突变体脂肪肝。scd-/-突变虽然不影响斑马鱼的雌雄性别分化和成熟配子的产生,但是影响雄性成鱼的生殖乳头发育缺陷,进而导致其自然交配行为缺陷。scd-/-突变体表现出的所有缺陷都可以通过全身性转基因过表达scd来挽救。总之,该研究首次表明scd对于维持斑马鱼的脂质稳态和雄性第二性征的发育是必不可少的,其与哺乳动物的表型差异可能是由于鱼类和哺乳动物营养利用方式的不同所致。

     

    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 scd in teleost fish remains unknown. Here, we generated a zebrafish scd mutant (scd-/-) to elucidate the role of scd in lipid metabolism and sexual development. Gas chromatography-mass spectrometry (GC-MS) showed that the scd -/- 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 Scd-/- mammals, the scd-/- zebrafish showed significantly increased fat accumulation in the whole body, especially in the liver, leading to hepatic mitochondrial dysfunction and severe cell apoptosis. Mechanistically, srebf1, a gene encoding a transcriptional activator related to adipogenesis, acc1 and acaca, genes involved in fatty acid synthesis, and dgat2, a key gene involved in triglyceride synthesis, were significantly upregulated in mutant livers to activate fatty acid biosynthesis and adipogenesis. The scd-/- males exhibited defective natural mating behavior due to defective genital papillae but possessed functional mature sperm. All defects in the scd-/- mutants could be rescued by ubiquitous transgenic overexpression of scd. In conclusion, our study demonstrates that scd is indispensable for maintaining lipid homeostasis and development of secondary sexual characteristics in zebrafish.

     

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