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

被引:35
作者
Abdulla, Arian [1 ]
Zhang, Yi [1 ]
Hsu, Fu-Ning [2 ]
Xiaoli, Alus M. [1 ]
Zhao, Xiaoping [1 ]
Yang, Ellen S. T. [1 ]
Ji, Jun-Yuan [2 ]
Yang, Fajun [1 ]
机构
[1] Albert Einstein Coll Med, Dept Med & Dev & Mol Biol, Diabet Res & Training Ctr, Bronx, NY 10461 USA
[2] Texas A&M Univ, Hlth Sci Ctr, Coll Med, Dept Mol & Cellular Med, College Stn, TX 77843 USA
基金
美国国家卫生研究院;
关键词
Lipid Metabolism; Lipogenesis; Sirtuin 1 (SIRT1); Transcription; Triglyceride; LSD1; SREBP1; ELEMENT-BINDING PROTEIN-1A; LEUCINE ZIPPER PROTEIN; LIPID-METABOLISM; TRANSCRIPTION FACTORS; SIRT1; DEACETYLATES; SREBP FAMILY; PHOSPHORYLATION; METHYLATION; MECHANISMS; TARGET;
D O I
10.1074/jbc.M114.573659
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Background: SREBP-1 plays a critical role in maintaining lipid homeostasis by activating lipogenic gene transcription. Results: LSD1 is required for SREBP1-mediated gene expression through multiple mechanisms in mammalian cells. Conclusion: LSD1 is a novel regulator of lipid metabolism. Significance: LSD1 is a potential target for treating diseases with aberrant lipid homeostasis. 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.
引用
收藏
页码:29937 / 29947
页数:11
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