The Role Of Hepatic Activating Transcription Factor 6 In Hepatic Lipid Metabolism

Obesity with AIDS, drug and alcohol abuse has developed of four life problems of the world, and is considered one of the most important problem in human health at present. Obesity itself is not fatal. Fatty liver, diabetes, hyperlipidemia, atherosclerosis easing to be complicated by obesity will reduce the real life. Liver disease associated with obesity caused by diets is becoming a hot spot of research at home and abroad.The liver is predominantly metabolism organ in the body. Oil produce glycerol and fatty acids by hydrolysis. Then fatty acid can generate CO2 and water on the condition of sufficient oxygen, and then release a lot of energy for the body to use. Fatty acid oxidation is the most active in the liver and muscle and the main form is beta oxidation. Berrant fatty acid metabolism plays important roles in the development of hepatic steatosis. Hepatic steatosis is increases in defective fatty acid metabolism, reflecting chronic increase in endoplasmic reticculum(ER)stress. However, whether the unfolded protein response(UPR), as an adaptive response by ER stress, also modulates fatty acid metabolism is unclear.Here we show that the nuclear receptor PPARαcouples the UPR and hepatic fatty acid metabolism. Pharmacological or genetic activation of the UPR using tunicamycin and thapsigargin, or by overexpression of active N-terminal domain of ATF6 respectively triggered activation of PPARα downstream targets, such as CPT1α and MCAD, the maker of mitochondrial fatty acid oxidation in Hep G2 cells. Conversel y, attenuation of the UPR using an adenovirus-delivered dominant negative form of ATF6(DN-ATF6), the unfolded protein response transducer, inhibited PPARα agonist WY 14643- or thapsigargin-induced fatty acid oxidation gene expression in epatocytes. Using the obese mice model induced by high fat and sugar diet, DN-ATF6 mice have increasing in body weight and liver weight/body weight; and a significant reduction in glucose tolerance and insulin sensitivity. Mover, triglyceride and cholesterol are significantly increased. HE dyeing experiments showed hepatic steatosis, Oil red O test showed an increased lipid drops, the UPR related gene expression significantly lowered by westen blotting. Interestingly, GST pull-down assays s howed tha t ATF6 p hysically interac te d with PPARα. C hr o ma ti n coprecipitation experiments showed: ATF6 with PPAR alpha and activation of transcription factors combine together to FGF21 upstream, regulate the expression of FGF21. Its transcriptional activity of 3×PPRE-driven reporter induced by PPARα/RXR complex or WY14643, and inhibited oxygen consumption rates in Hep G2 cells.These data indicate that ATF6 is necessary for transcriptional activity of PPARαand hepatic mitochondrial fatty acid oxidation. Because knockdown of ATF6 potently attenuated the UPR gene expression, such as GRP78 and CHOP, and exacerbated diet-induced hepatic steatosis, our results demonstrate 1) how cross-talk between the UPR and nuclear receptor coordinates at the transcriptional level, and contributes to hepatic lipid homeostasis; 2) modulation of the UPR through ATF6 represents an alternative avenue to improve liver function and treat hepatic steatosis in obesity.