Ozcan Lale, Ghorpade Devram S, Zheng Ze, de Souza Jane Cristina, Chen Ke, Bessler Marc, Bagloo Melissa, Schrope Beth, Pestell Richard, Tabas Ira
Department of Medicine, Columbia University, New York, NY 10032, USA.
Department of Medicine, Columbia University, New York, NY 10032, USA.
Cell Rep. 2016 Jun 7;15(10):2214-2225. doi: 10.1016/j.celrep.2016.05.006. Epub 2016 May 26.
Defective insulin signaling in hepatocytes is a key factor in type 2 diabetes. In obesity, activation of calcium/calmodulin-dependent protein kinase II (CaMKII) in hepatocytes suppresses ATF6, which triggers a PERK-ATF4-TRB3 pathway that disrupts insulin signaling. Elucidating how CaMKII suppresses ATF6 is therefore essential to understanding this insulin resistance pathway. We show that CaMKII phosphorylates and blocks nuclear translocation of histone deacetylase 4 (HDAC4). As a result, HDAC4-mediated SUMOylation of the corepressor DACH1 is decreased, which protects DACH1 from proteasomal degradation. DACH1, together with nuclear receptor corepressor (NCOR), represses Atf6 transcription, leading to activation of the PERK-TRB3 pathway and defective insulin signaling. DACH1 is increased in the livers of obese mice and humans, and treatment of obese mice with liver-targeted constitutively nuclear HDAC4 or DACH1 small hairpin RNA (shRNA) increases ATF6, improves hepatocyte insulin signaling, and protects against hyperglycemia and hyperinsulinemia. Thus, DACH1-mediated corepression in hepatocytes emerges as an important link between obesity and insulin resistance.
肝细胞中胰岛素信号缺陷是2型糖尿病的关键因素。在肥胖状态下，肝细胞中钙/钙调蛋白依赖性蛋白激酶II（CaMKII）的激活会抑制ATF6，从而触发PERK-ATF4-TRB3通路，该通路会破坏胰岛素信号。因此，阐明CaMKII如何抑制ATF6对于理解这一胰岛素抵抗通路至关重要。我们发现，CaMKII会磷酸化并阻止组蛋白去乙酰化酶4（HDAC4）的核转位。结果，HDAC4介导的辅阻遏物DACH1的SUMO化减少，这保护DACH1免受蛋白酶体降解。DACH1与核受体辅阻遏物（NCOR）一起抑制Atf6转录，导致PERK-TRB3通路激活和胰岛素信号缺陷。肥胖小鼠和人类肝脏中的DACH1增加，用肝脏靶向的组成型核HDAC4或DACH1小发夹RNA（shRNA）治疗肥胖小鼠可增加ATF6，改善肝细胞胰岛素信号，并预防高血糖和高胰岛素血症。因此，肝细胞中DACH1介导的共抑制作用成为肥胖与胰岛素抵抗之间的重要联系。
