Dataset Information

Identification of novel genes and pathways regulating SREBP transcriptional activity.

ABSTRACT:

Background

Lipid metabolism in mammals is orchestrated by a family of transcription factors called sterol regulatory element-binding proteins (SREBPs) that control the expression of genes required for the uptake and synthesis of cholesterol, fatty acids, and triglycerides. SREBPs are thus essential for insulin-induced lipogenesis and for cellular membrane homeostasis and biogenesis. Although multiple players have been identified that control the expression and activation of SREBPs, gaps remain in our understanding of how SREBPs are coordinated with other physiological pathways.

Methodology

To identify novel regulators of SREBPs, we performed a genome-wide cDNA over-expression screen to identify proteins that might modulate the transcription of a luciferase gene driven from an SREBP-specific promoter. The results were verified through secondary biological assays and expression data were analyzed by a novel application of the Gene Set Enrichment Analysis (GSEA) method.

Conclusions/significance

We screened 10,000 different cDNAs and identified a number of genes and pathways that have previously not been implicated in SREBP control and cellular cholesterol homeostasis. These findings further our understanding of lipid biology and should lead to new insights into lipid associated disorders.

SUBMITTER: Chatterjee S

PROVIDER: S-EPMC2668173 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Publications

Identification of novel genes and pathways regulating SREBP transcriptional activity.

Chatterjee Sandipan S Szustakowski Joseph D JD Nanguneri Nirmala R NR Mickanin Craig C Labow Mark A MA Nohturfft Axel A Dev Kumlesh K KK Sivasankaran Rajeev R

PloS one 20090421 4

<h4>Background</h4>Lipid metabolism in mammals is orchestrated by a family of transcription factors called sterol regulatory element-binding proteins (SREBPs) that control the expression of genes required for the uptake and synthesis of cholesterol, fatty acids, and triglycerides. SREBPs are thus essential for insulin-induced lipogenesis and for cellular membrane homeostasis and biogenesis. Although multiple players have been identified that control the expression and activation of SREBPs, gaps ...[more]

PMID: 19381295

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Project description:The ability of the aryl hydrocarbon receptor (AHR) to alter hepatic expression of cholesterol synthesis genes in a DRE-independent manner in mice and humans has been reported. We have examined the influence of functionally distinct classes of AHR ligands on the levels of Niemann-Pick C1-like intracellular cholesterol transporter (NPC1L1) and enzymes involved in the cholesterol synthesis pathway. NPC1L1 is known to mediate the intestinal absorption of dietary cholesterol and is clinically targeted. AHR ligands were capable of attenuating cholesterol uptake through repression of NPC1L1 expression. Through mutagenesis experiments targeting the two DRE sequences present in the promoter region of the NPC1L1 gene, we provide evidence that the repression does not require functional DRE sequences; while knockdown experiments demonstrated that this regulation is dependent on AHR and sterol-regulatory element-binding protein-2 (SREBP-2). Furthermore, upon ligand activation of AHR, the human intestinal Caco-2 cell line revealed coordinate repression of both mRNA and protein levels for a number of the cholesterol biosynthetic enzymes. Transcription of NPC1L1 and genes of the cholesterol synthesis pathway is predominantly regulated by SREBP-2, especially after treatment with a statin. Immunoblot analyses revealed a significant decrease in transcriptionally active SREBP-2 levels upon ligand treatment, whereas the precursor form of SREBP-2 was modestly increased by AHR activation. Mechanistic insights indicate that AHR induces proteolytic degradation of mature SREBP-2 in a calcium-dependent manner, which correlates with the AHR ligand-mediated upregulation of the transient receptor potential cation channel subfamily V member 6 (TRPV6) gene encoding for a membrane calcium channel. These observations emphasize a role for AHR in the systemic homeostatic regulation of cholesterol synthesis and absorption, indicating the potential use of this receptor as a target for the treatment of hyperlipidosis-associated metabolic diseases.

Dataset Information

Identification of novel genes and pathways regulating SREBP transcriptional activity.

Background

Methodology

Conclusions/significance

Publications

Identification of novel genes and pathways regulating SREBP transcriptional activity.

Similar Datasets

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