Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Cell Mol Med. 2019 May;23(5):3616-3628. doi: 10.1111/jcmm.14262. Epub 2019 Mar 1.
The Hippo pathway is an evolutionarily conserved regulator of organ size and tumorigenesis that negatively regulates cell growth and survival. Whether the Hippo pathway regulates cell metabolism is unknown. Here, we report that in the nucleus of hepatocytes, Yes-associated protein(YAP)-the terminal effector of the Hippo pathway-directly interacts with sterol regulatory element binding proteins (SREBP-1c and SREBP-2) on the promoters of the fatty acid synthase (FAS) and 30-hydroxylmethyl glutaryl coenzyme A reductase (HMGCR), thereby stimulating their transcription and promoting hepatocyte lipogenesis and cholesterol synthesis. In diet-induced diabetic mice, either Lats1 overexpression or YAP knockdown protects against hepatic steatosis and hyperlipidaemia through suppression of the interaction between YAP and SREBP-1c/SREBP-2. These results suggest that YAP is a nuclear co-factor of SREBPs and that the Hippo pathway negatively affects hepatocyte lipogenesis by inhibiting the function of YAP-SREBP complexes.
Hippo 通路是一种进化上保守的器官大小和肿瘤发生调节剂，它负调控细胞生长和存活。Hippo 通路是否调节细胞代谢尚不清楚。在这里，我们报告在肝细胞的核内，Hippo 通路的末端效应物 Yes 相关蛋白（YAP）直接与脂肪酸合酶（FAS）和 3-羟甲基戊二酰辅酶 A 还原酶（HMGCR）启动子上的固醇调节元件结合蛋白（SREBP-1c 和 SREBP-2）相互作用，从而刺激它们的转录，促进肝细胞的脂肪生成和胆固醇合成。在饮食诱导的糖尿病小鼠中，Lats1 的过表达或 YAP 的敲低通过抑制 YAP 和 SREBP-1c/SREBP-2 之间的相互作用，防止肝脂肪变性和高脂血症。这些结果表明，YAP 是 SREBPs 的核共因子，Hippo 通路通过抑制 YAP-SREBP 复合物的功能来负调控肝细胞的脂肪生成。
Zotero 插件
