Regulation of Lipid Homeostasis by the Histone Demethylase LSD1 and its Inhibitors

Abstract

Dysregulation of lipid homeostasis is a common feature of major human diseases, including cardiovascular disease and Type 2 Diabetes. As key activators of lipogenic genes, including fatty acid synthase ( FAS), sterol regulatory element-binding proteins (SREBPs) play a crucial role in regulating lipid homeostasis. Recent studies have shown that SREBPs are regulated by the NAD-dependent histone deacetylase SIRT1. SIRT1 has been shown to form a complex with the lysine-specific histone demethylase 1 (LSD1). Thus, we hypothesized that LSD1 regulates lipid metabolism through modulating SREBP-mediated gene expression. In this study, we show that LSD1 regulates SREBP-mediated gene expression through multiple mechanisms. Multiple lines of evidence suggest that LSD1 is required for SREBP-dependent activation of the FAS promoter in human cells. LSD1 knockdown impairs SREBP-1a binding to the FAS promoter without affecting the activity of the transactivation domain. In addition, LSD1 knockdown also specifically inhibits the SREBP-1a promoter activity in cultured cells resulting in a decrease of SREBP-1a mRNA levels. In HepG2 cells and primary hepatocytes, LSD1 knockdown significantly lowered triglyceride accumulation. Thus, we have identified a novel role of LSD1 in lipid metabolism, and our results suggest LSD1 as a potential target for treating diseases with aberrant lipid homeostasis.;In addition, we have also identified some natural compounds as novel LSD1 inhibitors, One of such compounds, resveratrol, has been previously proposed although it is controversial as a SIRT1 activator, and several studies have reported that resveratrol inhibits lipogenesis. Since resveratrol has been shown to be a known inhibitor of lipogenesis, we hypothesized that resveratrol-mediated inhibition of lipogenesis could be through inhibiting LSD1. Indeed, our data show that resveratrol inhibits LSD1 activity in vitro and in culture cells. Taken together, our data support the hypothesis that LSD1 plays a critical role in regulating lipogenesis, and LSD1 inhibitors could provide a novel approach for treating metabolic syndrome. In conclusion, we have learned about the role of LSD1 in regulating SREBP functions and how this regulation affects lipid synthesis in mammalian cells. Our studies further contribute to the understanding of lipid homeostasis, revealing novel mechanisms that could serve as potential future targets of therapeutic intervention.