Regulation of Lipogenic Gene Expression by Lysine-Specific Histone Demethylase-1 (LSD1) [Gene Regulation]

September 4th, 2014 by Abdulla, A., Zhang, Y., Hsu, F.-N., Xiaoli, A. M., Zhao, X., Yang, E. S. T., Ji, J.-Y., Yang, F.

Dysregulation of lipid homeostasis is a common feature of several major human dis-eases, including type 2 diabetes and cardiovas-cular disease. However, due to the complex na-ture of lipid metabolism, the regulatory mecha-nisms remain poorly defined at the molecular level. As the key transcriptional activators of lipogenic genes, such as fatty acid synthase (FAS), sterol regulatory element-binding pro-teins (SREBPs) play a pivotal role in stimulat-ing lipid biosynthesis. Several studies have shown that SREBPs are regulated by the NAD+-dependent histone deacetylase SIRT1, which forms a complex with the lysine-specific histone demethylase LSD1. Here, we show that LSD1 plays a role in regulating SREBP1-mediated gene expression. Multiple lines of evi-dence suggest that LSD1 is required for SREBP1-dependent activation of the FAS pro-moter in mammalian cells. LSD1 knockdown decreases SREBP-1a at the transcription level. Although LSD1 affects nuclear SREBP-1 abundance indirectly through SIRT1, it is also required for SREBP1-binding to the FAS pro-moter. As a result, LSD1 knockdown decreases triglyceride levels in hepatocytes. Taken togeth-er, these results show that LSD1 plays a role in regulating lipogenic gene expression, suggesting LSD1 as a potential target for treating dysregu-lation of lipid metabolism.