Regulation of Lipogenic Gene Expression by Lysine-specific Histone Demethylase-1 (LSD1)

Arian Abdulla,Alus M Xiaoli,Fajun Yang,Ellen S.T Yang,Yi Zhang,Jun-Yuan Ji,Fu-Ning Hsu,Xiaoping Zhao

doi:10.1074/jbc.m114.573659

Abstract

Dysregulation of lipid homeostasis is a common feature of several major human diseases, including type 2 diabetes and cardiovascular disease. However, because of the complex nature of lipid metabolism, the regulatory mechanisms 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 proteins (SREBPs) play a pivotal role in stimulating 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 evidence suggest that LSD1 is required for SREBP1-dependent activation of the FAS promoter 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 promoter. As a result, LSD1 knockdown decreases triglyceride levels in hepatocytes. Taken together, these results show that LSD1 plays a role in regulating lipogenic gene expression, suggesting LSD1 as a potential target for treating dysregulation of lipid metabolism.

Highlights

sterol regulatory element-binding proteins (SREBPs)-1 plays a critical role in maintaining lipid homeostasis by activating lipogenic gene transcription
LSD1 Regulates the Expression of fatty acid synthase (FAS) and SREBP-1a—To examine whether LSD1 could regulate lipogenic gene expression, we knocked down LSD1 in HEK293 cells using lentivirusbased LSD1-specific shRNA (Fig. 1A) and found that the mRNA levels of the FAS gene were significantly lower than those in control cells treated with NS-shRNA (Fig. 1B)
When the SREBP1-responsive elements were destroyed by point mutations, the promoter activity was expectedly decreased by ϳ70%, and more importantly, the effect of LSD1 knockdown vanished (Fig. 1C), suggesting that LSD1 is required for activating the FAS promoter in HEK293 cells and that such regulation is likely SREBP1-dependent

Summary

Background

SREBP-1 plays a critical role in maintaining lipid homeostasis by activating lipogenic gene transcription. As the key transcriptional activators of lipogenic genes, such as fatty acid synthase (FAS), sterol regulatory element-binding proteins (SREBPs) play a pivotal role in stimulating lipid biosynthesis. LSD1 knockdown decreases triglyceride levels in hepatocytes Taken together, these results show that LSD1 plays a role in regulating lipogenic gene expression, suggesting LSD1 as a potential target for treating dysregulation of lipid metabolism. Genetic manipulation of SIRT1 levels in mice results in altered triglyceride and cholesterol levels in serum and liver [23,24,25,26,27] These studies show that SIRT1 inhibition of SREBP target gene expression plays a conserved role in regulating lipid homeostasis. We show that LSD1 regulates SREBP1-mediated lipogenic gene expression at multiple steps

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION