1. Hepatic ATF6 Increases Fatty Acid Oxidation to Attenuate Hepatic Steatosis in Mice Through Peroxisome Proliferator-Activated Receptor α
- Author
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Yixuan Sun, Aoyuan Cui, Xin Gao, Yamei Han, Yingying Le, Feifei Zhang, Zhimin Hu, Qi Gong, Xianfu Gao, Yu Li, Zhengshuai Liu, Xuqing Chen, Zhongnan Yang, Jing Gao, Lily Q. Dong, and Shu Zhuo
- Subjects
0301 basic medicine ,Male ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Peroxisome proliferator-activated receptor ,Biology ,Retinoid X receptor ,03 medical and health sciences ,Mice ,Oxygen Consumption ,Internal medicine ,Insulin-Secreting Cells ,Internal Medicine ,medicine ,Animals ,PPAR alpha ,Obesity ,Beta oxidation ,chemistry.chemical_classification ,ATF6 ,Fatty liver ,Fatty Acids ,Fasting ,Peroxisome ,medicine.disease ,Lipid Metabolism ,Activating Transcription Factor 6 ,Diet ,Mitochondria ,Fatty Liver ,030104 developmental biology ,Endocrinology ,chemistry ,Liver ,Body Composition ,Hepatocytes ,RNA Interference ,Liver function ,Steatosis - Abstract
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 α (PPARα)/retinoid X receptor complex, and inhibits oxygen consumption rates in hepatocytes, possibly through inhibition of the binding of PPARα to the promoter of its target gene. Intriguingly, ATF6 physically interacts with PPARα, enhances the transcriptional activity of PPARα, and triggers activation of PPARα downstream targets, such as CPT1α 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 PPARα 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.
- Published
- 2015