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J Biol Chem. 2014 Oct 24;289(43):29937-47. doi: 10.1074/jbc.M114.573659. Epub 2014 Sep 4.

Regulation of lipogenic gene expression by lysine-specific histone demethylase-1 (LSD1).

Author information

1
From the Department of Medicine and Developmental & Molecular Biology, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461 and.
2
the Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University Health Science Center, College Station, Texas 77843.
3
From the Department of Medicine and Developmental & Molecular Biology, Diabetes Research and Training Center, Albert Einstein College of Medicine, Bronx, New York 10461 and fajun.yang@einstein.yu.edu.

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.

KEYWORDS:

LSD1; Lipid Metabolism; Lipogenesis; SREBP1; Sirtuin 1 (SIRT1); Transcription; Triglyceride

PMID:
25190802
PMCID:
PMC4208003
DOI:
10.1074/jbc.M114.573659
[Indexed for MEDLINE]
Free PMC Article

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