| RRC ID |
65438
|
| 著者 |
Khan AA, Sundar P, Natarajan B, Gupta V, Arige V, Reddy SS, Barthwal MK, Mahapatra NR.
|
| タイトル |
An evolutionarily-conserved promoter allele governs HMG-CoA reductase expression in spontaneously hypertensive rat.
|
| ジャーナル |
J Mol Cell Cardiol
|
| Abstract |
3-Hydroxy-3-methyl glutaryl-coenzyme A reductase (Hmgcr) encodes the rate-limiting enzyme in the cholesterol biosynthesis pathway. The regulation of Hmgcr in rat models of genetic hypertension (viz. Spontaneously Hypertensive Rats [SHR] and its normotensive control Wistar/Kyoto [WKY] strain) is unclear. Interestingly, Hmgcr transcript and protein levels are diminished in liver tissues of SHR as compared to WKY. This observation is consistent with the diminished plasma cholesterol level in SHR animals. However, the molecular basis of these apparently counter-intuitive findings remains completely unknown. Sequencing of the Hmgcr promoter in SHR and WKY strains reveals three variations: A-405G, C-62 T and a 11 bp insertion (-398_-388insTGCGGTCCTCC) in SHR. Among these variations, A-405G occurs at an evolutionarily-conserved site among many mammals. Moreover, SHR-Hmgcr promoter displays lower activity than WKY-Hmgcr promoter in various cell lines. Transient transfections of Hmgcr-promoter mutants and in silico analysis suggest altered binding of Runx3 and Srebf1 across A-405G site. On the other hand, C-62 T and -398_-388insTGCGGTCCTCC variations do not appear to contribute to the reduced Hmgcr promoter activity in SHR as compared to WKY. Indeed, chromatin immunoprecipitation assays confirm differential binding of Runx3 and Srebf1 to Hmgcr promoter leading to reduced expression of Hmgcr in SHR as compared to WKY under basal as well as cholesterol-modulated conditions. Taken together, this study provides, for the first time, molecular basis for diminished Hmgcr expression in SHR animals, which may account for the reduced circulating cholesterol level in this widely-studied model for cardiovascular diseases.
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| 巻・号 |
158
|
| ページ |
140-152
|
| 公開日 |
2021-9-1
|
| DOI |
10.1016/j.yjmcc.2021.05.017
|
| PII |
S0022-2828(21)00111-5
|
| PMID |
34081950
|
| MeSH |
Alleles*
Animals
CHO Cells
Core Binding Factor Alpha 3 Subunit / genetics
Cricetulus
Female
Gene Expression*
Gene Expression Regulation*
HEK293 Cells
Hep G2 Cells
Humans
Hydroxymethylglutaryl CoA Reductases / genetics*
Hypertension / enzymology*
Hypertension / genetics*
Male
Promoter Regions, Genetic / genetics*
Rats
Rats, Inbred SHR
Rats, Inbred WKY
Sterol Regulatory Element Binding Protein 1 / genetics
Transfection
|
| IF |
4.133
|
| リソース情報 |
| ラット |
In order to test if other genetically-inbred hypertensive rat strains also exhibit diminished serum cholesterol levels with respect to their controls, we retrieved serum total cholesterol and systolic blood pressure values of 21 strains from the National BioResource Project- Rat (http://www.anim.med.kyoto-u.ac.jp/nbr/) and PhenoMiner tool of the Rat Genome Database (RGD; http://rgd.mcw.edu/rgdweb/search/qtls.html?100) (Table S3). |
