Hepatic ATF6 Increases Fatty Acid Oxidation to Attenuate Hepatic Steatosis in Mice Through Peroxisome Proliferator-Activated Receptor α
Hepatic ATF6 Increases Fatty Acid Oxidation to Attenuate Hepatic Steatosis in Mice Through Peroxisome Proliferator-Activated Receptor α
复制标题
肝脏 ATF6 通过过氧化物酶体增殖物激活受体 α 增加脂肪酸氧化，减轻小鼠肝脏脂肪变性
作者：
Chen, Xuqing;Zhang, Feifei;Li, Yu
内质网质量控制蛋白激活转录因子6 （ATF6）是一种新的代谢调节因子。在这里，我们发现腺病毒介导的ATF6的显性阴性形式（dnATF6）的过表达增加了饮食诱导的胰岛素抵抗小鼠和禁食小鼠发生肝脂肪变性的易感性。dnATF6过表达或小干扰rna介导的ATF6敲低可降低过氧化物酶体增殖体激活受体α (PPAR α)/类视黄醇X受体复合物的转录活性，并抑制肝细胞的耗氧量，这可能是通过抑制PPAR α与其靶基因启动子的结合而实现的。有趣的是，ATF6与PPAR α物理相互作用，增强PPAR α的转录活性，并触发PPAR α下游靶点的激活，如肝细胞中的CPT-1 α和MCAD。此外，在饮食诱导的胰岛素抵抗小鼠中，肝脏过表达活性形式的ATF6促进肝脏脂肪酸氧化，并保护肝脏免受脂肪变性。这些数据描述了ATF6控制PPAR α和肝线粒体脂肪酸氧化活性的机制。因此，激活ATF6的策略可以作为改善肝功能和治疗肥胖肝脂肪变性的替代途径。
The endoplasmic reticulum quality control protein activating transcription factor 6 (ATF6) has emerged as a novel metabolic regulator. Here, we show that adenovirus-mediated overexpression of the dominant-negative form of ATF6 (dnATF6) increases susceptibility to develop hepatic steatosis in diet-induced insulin-resistant mice and fasted mice. Overexpression of dnATF6 or small interfering RNA-mediated knockdown of ATF6 decreases the transcriptional activity of peroxisome proliferator-activated receptor alpha (PPAR alpha)/retinoid X receptor complex, and inhibits oxygen consumption rates in hepatocytes, possibly through inhibition of the binding of PPAR alpha to the promoter of its target gene. Intriguingly, ATF6 physically interacts with PPAR alpha, enhances the transcriptional activity of PPAR alpha, and triggers activation of PPAR alpha downstream targets, such as CPT-1 alpha and MCAD, in hepatocytes. Furthermore, hepatic overexpression of the active form of ATF6 promotes hepatic fatty acid oxidation and protects against hepatic steatosis in diet-induced insulin-resistant mice. These data delineate the mechanism by which ATF6 controls the activity of PPAR alpha and hepatic mitochondria fatty acid oxidation. Therefore, strategies to activate ATF6 could be used as an alternative avenue to improve liver function and treat hepatic steatosis in obesity.