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 Rat [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-62T 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-62T 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.

3-Hydroxy-3-methyl glutaryl-coenzyme A 还原酶 ( Hmgcr ) 编码胆固醇生物合成途径中的限速酶。Hmgcr在遗传性高血压大鼠模型（即自发性高血压大鼠 [SHR] 及其正常血压对照 Wistar/Kyoto [WKY] 菌株）中的调节尚不清楚。有趣的是，与 WKY 相比，SHR 肝组织中的Hmgcr 转录物和蛋白质水平降低。这一观察结果与SHR 动物血浆胆固醇水平降低一致。然而，这些明显违反直觉的发现的分子基础仍然完全未知。Hmgcr的测序SHR 和 WKY 菌株中的启动子揭示了三种变异：A-405G、C-62T 和 SHR 中的 11 bp 插入 (‐398_-388insTGCGGTCCTCC)。在这些变异中，A-405G 出现在许多哺乳动物的进化保守位点。此外，在各种细胞系中，SHR- Hmgcr启动子的活性低于 WKY -Hmgcr启动子。Hmgcr -启动子突变体的瞬时转染和计算机分析表明 Runx3 和 Srebf1 在 A-405G 位点的结合发生了改变。另一方面，与 WKY 相比，C-62T 和 -398_-388insTGCGGTCCTCC 变异似乎不会导致SHR 中Hmgcr启动子活性降低。事实上，染色质免疫沉淀分析证实了 Runx3 和 Srebf1 与与基础条件和胆固醇调节条件下的 WKY 相比，Hmgcr启动子导致 SHR 中Hmgcr的表达降低。总之，这项研究首次为SHR 动物中Hmgcr表达减少提供了分子基础，这可能解释了这种广泛研究的心血管疾病模型中循环胆固醇水平降低的原因。