Hyperlipidemia and hepatitis in liver-specific CREB3L3 knockout mice generated using a one-step CRISPR/Cas9 system.
Hyperlipidemia and hepatitis in liver-specific CREB3L3 knockout mice generated using a one-step CRISPR/Cas9 system.
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DOI：
10.1038/srep27857
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发表时间：
2016-06-13
影响因子：
4.6
通讯作者：
Shimano H
中科院分区：
文献类型：
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作者：
Nakagawa Y;Oikawa F;Mizuno S;Ohno H;Yagishita Y;Satoh A;Osaki Y;Takei K;Kikuchi T;Han SI;Matsuzaka T;Iwasaki H;Kobayashi K;Yatoh S;Yahagi N;Isaka M;Suzuki H;Sone H;Takahashi S;Yamada N;Shimano H
cAMP反应元件结合蛋白3样3（CREB 3L 3）是一种在肝脏和小肠中表达的转录因子，其控制着空腹反应能量稳态。组织特异性CREB 3L 3敲除小鼠至今尚未产生。据我们所知，这是第一项使用一步CRISPR/Cas9系统来产生CREB 3L 3 floxed小鼠并随后获得肝脏和小的精氨酸特异性Creb 3l 3敲除（分别为LKO和IKO）小鼠的研究。虽然LKO小鼠以及全球KO小鼠发展高胆固醇血症，但LKO小鼠表现出高胆固醇血症，而全球KO小鼠则表现出低胆固醇血症。LKO小鼠表现出肝脏Srebf 2及其相应靶基因的上调。IKO和floxed小鼠之间没有观察到表型差异。在喂食蛋氨酸-胆碱缺乏饮食的LKO小鼠中观察到严重的肝损伤，这是一种非酒精性脂肪性肝炎模型。这些结果提供了关于肝脏CREB 3L 3在血浆甘油三酯代谢中的作用以及肝脏和肠道CREB 3L 3对胆固醇代谢的贡献的新证据。
cAMP responsive element binding protein 3-like 3 (CREB3L3), a transcription factor expressed in the liver and small intestine, governs fasting-response energy homeostasis. Tissue-specific CREB3L3 knockout mice have not been generated till date. To our knowledge, this is the first study using the one-step CRISPR/Cas9 system to generate CREB3L3 floxed mice and subsequently obtain liver- and small intestine-specific Creb3l3 knockout (LKO and IKO, respectively) mice. While LKO mice as well as global KO mice developed hypertriglyceridemia, LKO mice exhibited hypercholesterolemia in contrast to hypocholesterolemia in global KO mice. LKO mice demonstrated up-regulation of hepatic Srebf2 and its corresponding target genes. No phenotypic differences were observed between IKO and floxed mice. Severe liver injury was observed in LKO mice fed a methionine-choline deficient diet, a model for non-alcoholic steatohepatitis. These results provide new evidence regarding the hepatic CREB3L3 role in plasma triglyceride metabolism and hepatic and intestinal CREB3L3 contributions to cholesterol metabolism.