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Hormonal and nutritional regulation of alternative CD36 transcripts in rat liver: a role for growth hormone in alternative exon usage
KTH, School of Biotechnology (BIO), Gene Technology.
KTH, School of Biotechnology (BIO), Biochemistry.
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2007 (English)In: BMC Molecular Biology, ISSN 1471-2199, Vol. 8, no 60, 12- p.Article in journal (Refereed) Published
Abstract [en]

Background: CD36 is a multiligand receptor involved in various metabolic pathways, including cellular uptake of long-chain fatty acids. Defect function or expression of CD36 can result in dyslipidemia or insulin resistance. We have previously shown that CD36 expression is female-predominant in rat liver. In the present study, hormonal and nutritional regulation of hepatic CD36 expression was examined in male and female rats. Since alternative transcription start sites have been described in murine and human Cd36, we investigated whether alternative CD36 transcripts are differentially regulated in rat liver during these conditions.

Results: Sequence information of the rat Cd36 5'-UTR was extended, showing that the gene structure of Cd36 in rat is similar to that previously described in mouse with at least two alternative first exons. The rat Cd36 exon 1a promoter was sequenced and found to be highly similar to murine and human Cd36. We show that alternative first exon usage is involved in the female-predominant expression of CD36 in rat liver and during certain hormonal states that induce CD36 mRNA abundance. Estrogen treatment or continuous infusion of growth hormone (GH) in male rats induced CD36 expression preferentially through the exon 1a promoter. Old age was associated with increased CD36 expression in male rats, albeit without any preferential first exon usage. Intermittent GH treatment in old male rats reversed this effect. Mild starvation (12 hours without food) reduced CD36 expression in female liver, whereas its expression was increased in skeletal muscle.

Conclusion: The results obtained in this study confirm and extend our previous observation that GH is an important regulator of hepatic CD36, and depending on the mode of treatment (continuous or intermittent) the gene might be either induced or repressed. We suggest that the effects of continuous GH secretion in females (which is stimulatory) and intermittent GH secretion in males (which is inhibitory) explains the sex-different expression of this gene. Furthermore, a female-specific repression of hepatic CD36 in response to food deprivation was found, which was in contrast to a stimulatory effect in skeletal muscle. This demonstrates a tissue-specific regulation of Cd36.

Place, publisher, year, edition, pages
2007. Vol. 8, no 60, 12- p.
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:kth:diva-7867DOI: 10.1186/1471-2199-8-60ISI: 000248476300001ScopusID: 2-s2.0-34547685783OAI: diva2:13018
QC 20100621Available from: 2007-12-19 Created: 2007-12-19 Last updated: 2012-03-20Bibliographically approved
In thesis
1. Computational and experimental approaches to regulatory genetic variation
Open this publication in new window or tab >>Computational and experimental approaches to regulatory genetic variation
2007 (English)Doctoral thesis, comprehensive summary (Other scientific)
Abstract [en]

Genetic variation is a strong risk factor for many human diseases, including diabetes, cancer, cardiovascular disease, depression, autoimmunity and asthma. Most of the disease genes identified so far alter the amino acid sequences of encoded proteins. However, a significant number of genetic variants affecting complex diseases may alter the regulation of gene transcription. The map of the regulatory elements in the human genome is still to a large extent unknown, and it remains a challenge to separate the functional regulatory genetic variations from linked neutral variations.

The objective of this thesis was to develop methods for the identification of genetic variation with a potential to affect the transcriptional regulation of human genes, and to analyze potential regulatory polymorphisms in the CD36 glycoprotein, a candidate gene for cardiovascular disease.

An in silico tool for the prediction of regulatory polymorphisms in human genes was implemented and is available at The tool was evaluated using experimentally verified regulatory single nucleotide polymorphisms (SNPs) collected from the scientific literature, and tested in combination with experimental detection of allele specific expression of target genes (allelic imbalance). Regulatory SNPs were shown to be located in evolutionary conserved regions more often than background SNPs, but predicted transcription factor binding sites were unable to enrich for regulatory SNPs unless additional information linking transcription factors with the target genes were available.

The in silico tool was applied to the CD36 glycoprotein, a candidate gene for cardiovascular disease. Potential regulatory SNPs in the alternative promoters of this gene were identified and evaluated in vitro and in vivo using a clinical study for coronary artery disease. We observed association to the plasma concentrations of inflammation markers (serum amyloid A protein and C-reactive protein) in myocardial infarction patients, which highlights the need for further analyses of potential regulatory polymorphisms in this gene.

Taken together, this thesis describes an in silico approach to identify putative regulatory polymorphisms which can be useful for directing limited laboratory resources to the polymorphisms most likely to have a phenotypic effect.

Place, publisher, year, edition, pages
Stockholm: Bioteknologi, 2007
Trita-BIO-Report, ISSN 1654-2312 ; 2007:12
Molecular biology, Genetics, single nucleotide polymprhism (SNP), regulatory SNP, transcription factor binding site, phylogenetic footprinting, allelic imbalance, EMSA, CD36, cardiovascular disease.
National Category
Other Industrial Biotechnology
urn:nbn:se:kth:diva-4593 (URN)978-91-7178-827-6 (ISBN)
Public defence
2008-01-18, FD5, AlbaNova Universitetscentrum, Roslagstullsbacken 21, Stockholm, 10:00
Available from: 2007-12-19 Created: 2007-12-19 Last updated: 2012-03-20Bibliographically approved

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