Elevated endoplasmic reticulum (ER) stress plays crucial roles in the development of insulin resistance, type 2 diabetes, and obesity. X-Box binding protein 1 (XBP1) is one of the master regulators of ER folding function and is involved in the regulation of ER stress. Haploinsufficiency of XBP1 leads to the development of obesity, insulin resistance, and type 2 diabetes even in mice on a background that is resistant to the development of obesity. To date, our understanding of the regulation of XBP1 in metabolic processes is still limited. In our previous work, we demonstrated that bromodomain containing protein 7 (BRD7) regulates glucose homeostasis by increasing the nuclear translocation of XBP1s through its interaction with the regulatory subunits of phosphatidyl inositol 3-kinase (PI3K), p85s. We also showed that BRD7 protein levels are significantly reduced in the liver of genetically obese ob/ob and high fat diet (HFD)-induced obese mouse models, and over-expression of BRD7 in the liver of ob/ob and HFD fed mice ameliorates hyperglycemia and glucose intolerance through increasing the activity of XBP1s. In our current unpublished work, we show that BRD7 heterozygous knockout mice are prone to developing obesity when they are challenged with a HFD. They display increased hepatic triglyceride levels with moderately severe steatosis. In addition, we generated a liver-specific BRD7 knockout mouse model (LBKO) to examine the effect of BRD7 specifically in the liver. LBKO mice fed on a HFD exhibit increased body weights compared to their wild type control mice. Downregulation of BRD7 in the liver led to lack of nuclear XBP1s in the liver in both the knockout mouse model and adenovirus-mediated knockdown system. Our results provide the first evidence that BRD7, which was originally reported as a tumor suppressor, is involved in the development of obesity as well as in the regulation of unfolded protein response (UPR) and glucose metabolism.
S. Park: None. Y. Han: None. M.A. Salazar Hernandez: None.