Transcriptional regulation of HMG-CoA synthase and HMG-CoA reductase genes by human ACBP.
The acyl-CoA binding protein (ACBP) is an ubiquitary expressed multi-functional protein which regulates basic cellular functions such as fatty acid and steroid metabolism. Since ACBP is described to interact with the transcription factor hepatocyte nuclear factor 4 alpha (HNF-4alpha), we investigated the role of human ACBP on transcriptional regulation of the putative HNF-4alpha target gene HMG-CoA synthase 1 (HMGCS1). As shown by promoter-reporter assays ACBP represses the HNF-4alpha-induced activity of a 617bp HMGCS1 promoter fragment by approximately 80% in HepG2 cells as well as in non-endodermal HeLa cells devoid of HNF-4alpha. Interestingly, reporter assays without co-transfection of HNF-4alpha revealed that ACBP reduces the activity of the HMGCS1 promoter by about 60 to 80% in both cell lines. Activities of 417bp and 317bp HMGCS1 promoter fragments were 2.5 to 4 fold decreased by ACBP. Concordantly, the levels of HMGCS1-mRNA and -protein were diminished to 60% and 70% in ACBP-expressing HeLa cells, respectively. Additionally, ACBP reduces the promoter activity and the mRNA levels of the cholesterogenic HMG-CoA reductase (HMGCR). In conclusion, we provide evidence that ACBP is a transcriptional regulator of the HMGCS1 and HMGCR genes encoding rate-limiting enzymes of cholesterol synthesis pathway.
Vock
Christina
C
Molecular Nutrition, Christian-Albrechts-University of Kiel, Kiel, Germany.
Döring
Frank
F
Nitz
Inke
I
D045744:Cell Line, Tumor; D002784:Cholesterol / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D026261:Diazepam Binding Inhibitor / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D006801:Humans; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics*; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D026261:Diazepam Binding Inhibitor; D051557:Hepatocyte Nuclear Factor 4; D012333:RNA, Messenger; D002784:Cholesterol; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D006904:Hydroxymethylglutaryl-CoA Synthase