Maturation and Activity of Sterol Regulatory Element Binding Protein 1 Is Inhibited by Acyl-CoA Binding Domain Containing 3

Yong Chen,Vishala Patel,Sookhee Bang,Natalie Cohen,Sangwon F Kim,John Millar,Hironori Waki

doi:10.1371/journal.pone.0049906

Yong Chen, Vishala Patel + Show 5 more

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https://doi.org/10.1371/journal.pone.0049906

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Journal: PLoS ONE	Publication Date: Nov 14, 2012
Citations: 74	License type: CC BY 4.0

Affiliation: University of Pennsylvania

Abstract

Imbalance of lipid metabolism has been linked with pathogenesis of a variety of human pathological conditions such as diabetes, obesity, cancer and neurodegeneration. Sterol regulatory element binding proteins (SREBPs) are the master transcription factors controlling the homeostasis of fatty acids and cholesterol in the body. Transcription, expression, and activity of SREBPs are regulated by various nutritional, hormonal or stressful stimuli, yet the molecular and cellular mechanisms involved in these adaptative responses remains elusive. In the present study, we found that overexpressed acyl-CoA binding domain containing 3 (ACBD3), a Golgi-associated protein, dramatically inhibited SREBP1-sensitive promoter activity of fatty acid synthase (FASN). Moreover, lipid deprivation-stimulated SREBP1 maturation was significantly attenuated by ACBD3. With cell fractionation, gene knockdown and immunoprecipitation assays, it was showed that ACBD3 blocked intracellular maturation of SREBP1 probably through directly binding with the lipid regulator rather than disrupted SREBP1-SCAP-Insig1 interaction. Further investigation revealed that acyl-CoA domain-containing N-terminal sequence of ACBD3 contributed to its inhibitory effects on the production of nuclear SREBP1. In addition, mRNA and protein levels of FASN and de novo palmitate biosynthesis were remarkably reduced in cells overexpressed with ACBD3. These findings suggest that ACBD3 plays an essential role in maintaining lipid homeostasis via regulating SREBP1's processing pathway and thus impacting cellular lipogenesis.

Highlights

Sterol regulatory element binding proteins (SREBPs) are a family of basic-helix-loop- helix leucine-zipper transcription factors
acyl-CoA binding domain containing 3 (ACBD3) inhibits SREBP1-promoted fatty acid synthase (FASN) transcription Since FASN is one SREBP1 target gene and an essential multifunction enzyme in the de novo fatty acid biosynthesis pathway [18], we employed a luciferase reporter vector, encoding a sterol regulatory element (SRE)-containing FASN promoter sequence fused with firefly luciferase to assess how ACBD3 overexpression changed FASN promoter activity
We found that full-length SREBP1Aboosted FASN promoter activity was significantly decreased by co-expressed ACBD3, suggesting this ACBD3-mediated inhibition of FASN promoter activity works through SREBP1 (Figure 1B)

Summary

Introduction

Sterol regulatory element binding proteins (SREBPs) are a family of basic-helix-loop- helix leucine-zipper (bHLH-LZ) transcription factors. There are three well-characterized SREBP isoforms in mammals: SREBP1A, SREBP1C and SREBP2 [1] They are the master regulators of lipid homeostasis in the cells through controlling expression of over 30 genes, such as fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), low-density lipoprotein receptor, HMG-CoA reductase, stearoyl-CoA desaturase, ATP citrate lysase and Glycerol-3-phosphate acyltransferase [2,3]. A recent report by Walker et al revealed that Sadenosylmethionine synthetase type 1, methylenetetrahydrofolate reductase, methionine synthase and several other related genes were regulated by SREBP1 [4] Those SREBP target genes are required for biosynthesis of fatty acid, cholesterol, triglyceride and phospholipids. SREBP2 causes a preferential induction of genes related to cholesterol biosynthesis [5,6]

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