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<p>Hypercholesterolemia is a leading cause of various cardiovascular diseases (CVDs). 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (Hmgcr) is the rate-limiting enzyme in the cholesterol biosynthesis pathway. Previous studies investigated the regulation of <i>Hmgcr</i> expression under various pathophysiological conditions. However, its expression under hypoxia, an important player in the pathogenesis of CVD, is poorly understood. The present study investigated the hepatic expression of Hmgcr and Hif-1α in Spontaneously hypertensive rats [SHR] and its normotensive control, Wistar Kyoto [WKY] rats. Interestingly, hepatic <i>Hmgcr</i> expression was diminished while <i>Hif-1α</i> expression was elevated in SHR. In cultured rat liver cells, the <i>Hmgcr</i> promoter activity/transcript/protein and intracellular cholesterol levels were diminished after hypoxia treatment. Further, while Hif-1α /Runx3 transcript and protein levels were enhanced, Srebf levels decreased upon hypoxia. Knock-down of Hif-1α abrogated the hypoxia-mediated effect on Hmgcr, intracellular cholesterol levels, and the expression of Srebf and Runx3. Chromatin immunoprecipitation (ChIP) assays showed binding of Hif-1α to both endogenous SHR- and WKY-<i>Hmgcr/Srebf/Runx3</i> domains with similar promoter occupancies. However, differential binding of Hif-1α to <i>Srebf</i> and <i>Runx3</i> promoter domains were observed from ChIP assay. While <i>HIF-1α</i> showed a negative correlation with <i>HMGCR</i>/<i>SREBF</i> transcript levels, it correlated positively with <i>RUNX3</i>. Additionally, ChIP assays demonstrated differential binding of Srebf and Runx3 to SHR/WKY-<i>Hmgcr</i> promoter domains upon hypoxic stress. Taken together, this study elucidates the regulatory role of Hif-1α in modulating <i>Hmgcr</i> expression and intracellular cholesterol levels via Srebf and Runx3 under hypoxic stress. These findings provide new mechanistic insights underlying cholesterol homeostasis under hypoxia.</p>

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Srebf and Runx3 regulate hepatic HMG-CoA reductase and intracellular cholesterol under hypoxia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月4日

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  • Sundar Poovitha,
  • Abrar A. Khan,
  • Silpa Arkat,
  • Anupama Vijayakumar,
  • Bhargavi Natarajan,
  • Manoj K. Barthwal,
  • Nitish R. Mahapatra

摘要

Hypercholesterolemia is a leading cause of various cardiovascular diseases (CVDs). 3-hydroxy-3-methylglutaryl-Coenzyme A reductase (Hmgcr) is the rate-limiting enzyme in the cholesterol biosynthesis pathway. Previous studies investigated the regulation of Hmgcr expression under various pathophysiological conditions. However, its expression under hypoxia, an important player in the pathogenesis of CVD, is poorly understood. The present study investigated the hepatic expression of Hmgcr and Hif-1α in Spontaneously hypertensive rats [SHR] and its normotensive control, Wistar Kyoto [WKY] rats. Interestingly, hepatic Hmgcr expression was diminished while Hif-1α expression was elevated in SHR. In cultured rat liver cells, the Hmgcr promoter activity/transcript/protein and intracellular cholesterol levels were diminished after hypoxia treatment. Further, while Hif-1α /Runx3 transcript and protein levels were enhanced, Srebf levels decreased upon hypoxia. Knock-down of Hif-1α abrogated the hypoxia-mediated effect on Hmgcr, intracellular cholesterol levels, and the expression of Srebf and Runx3. Chromatin immunoprecipitation (ChIP) assays showed binding of Hif-1α to both endogenous SHR- and WKY-Hmgcr/Srebf/Runx3 domains with similar promoter occupancies. However, differential binding of Hif-1α to Srebf and Runx3 promoter domains were observed from ChIP assay. While HIF-1α showed a negative correlation with HMGCR/SREBF transcript levels, it correlated positively with RUNX3. Additionally, ChIP assays demonstrated differential binding of Srebf and Runx3 to SHR/WKY-Hmgcr promoter domains upon hypoxic stress. Taken together, this study elucidates the regulatory role of Hif-1α in modulating Hmgcr expression and intracellular cholesterol levels via Srebf and Runx3 under hypoxic stress. These findings provide new mechanistic insights underlying cholesterol homeostasis under hypoxia.