The Role of Activating Transcription Factor 3 on Endoplasmic Reticulum Stress, Oxidative Stress, Visceral Fat Metabolism, and Inflammation in Fructose-Fed Hypertensive Mice

Our studies previously showed that oxidative stress in visceral adipose tissues contributed to fructose-induced hypertension and metabolic syndrome, and high-fructose feeding increased the activating transcription factor 3 (ATF3) expressions in the visceral fat pads. ATF3 has been reported to play a potential role in regulating inflammation and cardiovascular system. However, the role of ATF3 on oxidative stress, visceral fat metabolism and inflammation in fructose-fed hypertensive mice remains unclear in the literature. This three-year project is to examine the effects of ATF3 on endoplasmic reticulum (ER) stress, oxidative stress, and visceral fat metabolism in adipose cytoplasm; and further investigate the nucleus ATF3 regulation of peroxisome proliferator-activated receptors (PPARs), nuclear factor kB (NF-kB) and inflammation in fructose-fed hypertensive mice. For the first year, we will investigate the potential physiologic mechanisms of fructose-induced ATF3 activation. We hypothesize that fructose diet could evoke angiotensin II (Ang II), activating protein kinase C (PKC) lead to phosphorylation of p47phox allowing it’s binding to p22phox, then causing NADPH oxidase (NOX) activity and finally activating ER stress signaling (PERK, eIF2훼, ATF3). For the second year, because of increased ATF3 expression in visceral fat tissues by our preliminary data, we will investigate if fructose-induced ATF3 activation would regulate ER stress, reactive oxygen species, oxidative stress, and visceral fat metabolism. For the third year, we will investigate the role of ATF3 in adipose nucleus regulating peroxisome proliferator-activated receptors (PPARs), nuclear factor kB (NF-kB) and inflammation. Finally, this project will establish a basic research relationship between fructose-induced adiposity and ATF3 and bring the new perspective of ATF3 as a potential role in ER stress, oxidative stress, visceral fat metabolism, and inflammation in fructose-fed hypertensive mice.