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短链脂肪酸丁酸抑制动脉粥样硬化形成及其分子机制

白洪波¹, 杨萍², 张汉斌², 刘钰林², 方淑香², 许小洋^1,*

¹广州医科大学基础医学院生理教研室，广州 511436；²广州医科大学第二临床学院，广州 510260

摘要

本研究通过观察丁酸对动脉粥样硬化斑块形成以及肠道组织结构和功能的影响，探讨丁酸防治动脉粥样硬化的效应及可能机制。选取8周龄雄性载脂蛋白E基因敲除(apolipoprotein E-knockout, ApoE−/−)小鼠，随机分成对照组(高脂高胆固醇饲料+饮水中给予200 mmol/L氯化钠，n = 10)和丁酸组(高脂高胆固醇饲料+饮水中给予200 mmol/L丁酸钠，n = 10)，喂养12周。干预结束后麻醉处死小鼠并分离主动脉、心脏，油红O染色定量分析动脉粥样硬化斑块面积。取新鲜的小鼠肠道组织检测肠道组织长度、结构和通透性。定量PCR和酶联免疫吸附法检测炎症因子水平。结果表明：与对照组相比，丁酸组小鼠动脉粥样硬化斑块面积显著减少(P < 0.01)，血清总胆固醇和低密度脂蛋白胆固醇水平也明显降低(P < 0.05)，主动脉、肠道组织以及血液循环中炎症因子表达水平显著下降。同时，丁酸干预后小鼠肠道结构更加致密，肠道通透性降低，血液内毒素脂多糖水平也明显降低，肠道紧密连接蛋白Occludin和ZO-1基因表达水平显著升高。体外人小肠上皮细胞Caco-2实验结果显示，丁酸可以剂量依赖性地上调Occludin和ZO-1 mRNA和蛋白表达水平，这一效应可以被G蛋白耦联受体41小干扰RNA所阻断。以上结果提示，丁酸显著抑制小鼠动脉粥样硬化发生，其作用机制可能与其降低肠道通透性、减少血液脂多糖和炎症因子水平有关。

关键词： 短链脂肪酸; 丁酸; 动脉粥样硬化; 肠道通透性

分类号：R353

Short-chain fatty acid butyrate acid attenuates atherosclerotic plaque formation in apolipoprotein E-knockout mice and the underlying mechanism

BAI Hong-Bo¹, YANG Ping², ZHANG Han-Bin², LIU Yu-Lin², FANG Shu-Xiang², XU Xiao-Yang^1,*

¹Department of Physiology, School of Basic Medical Science, Guangzhou Medical University, Guangzhou 511436, China；²The Second Clinical School of Guangzhou Medical University, Guangzhou 510260, China

Abstract

This study was designed to evaluate the role of short-chain fatty acid butyrate acid on intestinal morphology and function, and atherosclerotic plaque formation in apolipoprotein E-knockout (ApoE−/−) mice. ApoE−/− mice on high-fat, high-cholesterol diet were treated with butyrate acid (200 mmol/L) or NaCl (control) in the drinking water for 12 weeks, followed by histological evaluations of atherosclerotic lesion in aorta. Real-time PCR analysis and ELISA were used to measure the expression levels of proinflammatory cytokines. Butyrate acid significantly attenuated high-fat, high-cholesterol diet-induced atherosclerotic plaque formation in ApoE−/− mice. Butyrate acid prevented high-fat, high-cholesterol diet-induced inflammation in both the aorta and the circulation, as evidenced by reduced expression of proinflammatory cytokines. These changes were accompanied by a marked attenuation in metabolic endotoxemia lipopolysaccharide (LPS). Butyrate acid induced intestinal expression of the tight junction proteins (Occludin and zona occuldens protein-1), thereby preventing the gut permeability. Butyrate acid dose-dependently upregulated the expression of the tight junction proteins in Caco-2 cells in GPR41-dependent manner. In conclusion, butyrate acid attenuates atherosclerotic lesions by ameliorating metabolic endotoxemia-induced inflammation through restoration of the gut barrier. 

Key words: short-chain fatty acid; butyrate acid; atherosclerosis; gut permeability

收稿日期：2020-03-13　　录用日期：2020-08-28

通讯作者：许小洋　　E-mail: xiaoyang-xu@gzhmu.edu.cn

DOI: 10.13294/j.aps.2020.0059

引用本文：

白洪波, 杨萍, 张汉斌, 刘钰林, 方淑香, 许小洋. 短链脂肪酸丁酸抑制动脉粥样硬化形成及其分子机制[J]. 生理学报 2021; 73 (1): 42-50.

BAI Hong-Bo, YANG Ping, ZHANG Han-Bin, LIU Yu-Lin, FANG Shu-Xiang, XU Xiao-Yang. Short-chain fatty acid butyrate acid attenuates atherosclerotic plaque formation in apolipoprotein E-knockout mice and the underlying mechanism. Acta Physiol Sin 2021; 73 (1): 42-50 (in Chinese with English abstract).