Hepatic Atf6 Increases Fatty Acid Oxidation To Attenuate Hepatic Steatosis In Mice Through Peroxisome Proliferator-Activated Receptor Alpha

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.