Taurine alleviates dysfunction of cholesterol metabolism under hyperuricemia by inhibiting A2AR-SREBP-2/CREB/HMGCR axis.

IF 5 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Journal of Lipid Research Pub Date : 2025-02-01 Epub Date: 2025-01-21 DOI:10.1016/j.jlr.2025.100746

Beibei Chen, Ruixia Bao, Jujie Pan, Zicheng Zhu, Qian Chen, Dan Wang, Yuzheng Wu, Haiyang Yu, Yi Zhang, Tao Wang

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Abstract

Dysfunctional cholesterol metabolism is highly prevalent in patients with hyperuricemia. Both uric acid and cholesterol are independent risk factors for atherosclerosis, contributing to an increased incidence of cardiovascular disease in hyperuricemia. Investigating the pathological mechanisms underlying cholesterol metabolism dysfunction in hyperuricemia is essential. This study identified adenosine and inosine, two major purine metabolites, as key regulators of cholesterol biosynthesis. These metabolites upregulate 3-hydroxy-3-methylglutaryl-CoA. Further mechanistic studies revealed that adenosine/inosine up-regulated the expression of 3-hydroxy-3-methylglutaryl-CoA by activating adenosine A2A receptor via the Srebp-2/Creb axis in hyperuricemia. Additionally, we found that taurine deficiency contributes to cholesterol metabolism dysfunction in hyperuricemia. Taurine administration in hyperuricemia mice significantly reduced cholesterol elevation by inhibiting adenosine A2A receptor. This study provides a promising strategy for treating comorbid hypercholesterolemia and hyperuricemia.

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牛磺酸通过抑制A2AR-SREBP-2/CREB/HMGCR轴减轻高尿酸血症时胆固醇代谢功能障碍。

胆固醇代谢功能紊乱在高尿酸血症患者中非常普遍。尿酸和胆固醇都是动脉粥样硬化的独立危险因素，导致高尿酸血症患者心血管疾病的发病率增加。研究高尿酸血症中胆固醇代谢功能障碍的病理机制是必要的。本研究确定了两种主要嘌呤代谢产物腺苷和肌苷作为胆固醇生物合成的关键调节因子。这些代谢物上调3-羟基-3-甲基戊二酰辅酶a （HMGCR）。进一步的机制研究表明，在高尿酸血症中，腺苷/肌苷通过固醇调节元件结合蛋白2 (SREBP-2)/CREB轴激活腺苷A2A受体（A2AR），从而上调HMGCR的表达。此外，我们发现牛磺酸缺乏有助于高尿酸血症的胆固醇代谢功能障碍。高尿酸血症小鼠给予牛磺酸可通过抑制A2AR显著降低胆固醇升高。本研究为治疗合并高胆固醇血症和高尿酸血症提供了一个有希望的策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Lipid Research 生物-生化与分子生物学

CiteScore

11.10

自引率

4.60%

发文量

146

审稿时长

41 days

期刊介绍： The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.

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