The function of SREBP‐1a in high sucrose diet‐mediated metabolic disease

The sterol regulatory element binding proteins (SREBPs) activate expression of key genes required for lipid metabolism and regulation. We established a line of mice that selectively reduces expression of SREBP‐1a (SREBP‐1aDF) leaving expression of the overlapping SREBP‐1c and unlinked SREBP‐2 transcripts unaffected. Our current study demonstrates that SREBP‐1a is involved in high sucrose diet‐mediated metabolic disease. We show SREBP‐1aDF mice become glucose intolerant and insulin resistant on high sucrose. Both GLUT4 protein and mRNA expression are decreased in muscle and adipose tissue of high sucrose fed SREBP‐1aDF mice. However, SREBP‐1aDF mice prevent high sucrose dependent hepatic steatosis even though mutant mice induce insulin resistance. We further find SREBP‐1aDF mice also reduce serum free fatty acid on high sucrose diet. High sucrose diet does not activate adipose triglyceride lipase and hormone‐sensitive lipase mRNA expression in adipose tissue from SREBP‐1aDF mice. Moreover, expression of tumor necrosis factor‐a is decreased in high sucrose fed mutant adipose tissue compared to wild‐type mice. Tumor necrosis factor‐a has known to be a regulator of lipolysis in adipose tissue. Those data indicate adipose lipolysis is reduced due to decrease of tumor necrosis factor‐a in SREBP‐1aDF mice, resulting in decreased serum free fatty acid. In a previous study, we already demonstrated that fatty acid oxidation was increased in SREBP‐1aDF mice due to reduction of acetyl‐coA carboxylase 2 in liver. Thus, those data suggest that SREBP‐1aDF mice are more susceptible to high sucrose diet‐mediated insulin resistance owing to decreases of both GLUT4 protein and mRNA expression. In addition, SREBP‐1aDF mice are protected from hepatic steatosis on high sucrose diet through altered lipolysis and fatty acid oxidation.