Fatty acid synthase knockout impairs early embryonic development via induction of endoplasmic reticulum stress in pigs

文献类型： 外文期刊

第一作者： Guo, Jing

作者： Guo, Jing;Niu, Ying-Jie;Shin, Kyung-Tae;Kwon, Jeong-Woo;Kim, Nam-Hyung;Cui, Xiang-Shun;Guo, Jing

作者机构：

关键词： apoptosis;CRISPR;Cas9;ER stress;FAS;ROS

期刊名称：JOURNAL OF CELLULAR PHYSIOLOGY （ 影响因子：6.384； 五年影响因子：5.987 ）

ISSN： 0021-9541

年卷期： 2018 年 233 卷 5 期

页码：

收录情况： SCI

摘要： Fatty acid synthase (FAS) is an important enzyme involved in the de novo synthesis of long-chain fatty acids. During development, the function of FAS in growth is greater than that in energy storage pathways; therefore, we hypothesized that knockout of FAS would affect early embryonic development owing to the induction of endoplasmic reticulum (ER) stress. In the present study, the function of FAS was studied using the CRISPR (clustered regularly interspaced short palindromic repeats)/ CRISPR-associated protein 9 (Cas9) system. Cas9 and single-guide RNA (sgRNA) were injected into parthenotes to decrease the number of FAS-positive embryos. The efficiency of knockout was assayed by DNA sequencing. We found that FAS knockout caused excessive production of reactive oxygen species (ROS). Excess ROS induced ER stress, resulting in activation of the adaptive unfolded protein response (UPR). FAS knockout caused splicing of the X-box binding protein 1 gene (XBP1) and expression of spliced XBP1 mRNA. In addition, FAS knockout caused phosphorylation of PKR-like ER kinase (PERK), and an increase in the mRNA expression of the ER stress-regulated genes, activating transcription factor 4 (ATF4), and C/EBP homologous protein (CHOP). Finally, Ca2+ was released from the ER and taken up by the mitochondria. As the ER stress became intolerable, apoptosis was initiated. These results demonstrate that FAS knockout induced ROS generation, which mediated the activation of UPR via the ER stress, ultimately leading to apoptosis induction.

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