Du Yu, Li Xingxing, Su Chunyan, Xi Mei, Zhang Xiumin, Jiang Zhibo, Wang Li, Hong Bin
NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Br J Pharmacol. 2020 Apr;177(8):1754-1772. doi: 10.1111/bph.14933. Epub 2020 Feb 12.
The gut microbial metabolite butyrate is linked to the modulation of metabolic disease. The mechanism by which butyrate effects in atherosclerosis is unknown. Hence, the present investigation into effects of butyrate on high-fat diet-fed ApoE mice after 16 weeks' administration.
Gut microbiota composition was analysed via 16S rRNA gene sequencing of caecal contents. The effects of butyrate on atherosclerosis were evaluated in vivo using the ApoE mice model. Serum lipids and glucose were analysed for physiological changes and differentially expressed genes in liver samples were identified by hepatic transcriptome profiling. The proteins involved in reverse cholesterol transport were quantified by Western blot and immunohistochemical staining. Finally, the up-regulatory effects of butyrate on ATP-binding cassette sub-family A member 1 (ABCA1) were further evaluated in RAW 264.7 cells along with role of specificity protein 1 by inhibition and silencing.
Oral gavage of butyrate altered microbiota composition and enhanced gut microbial diversity that was decreased by high fat diet (HFD). Butyrate treatment significantly inhibited the HFD-induced atherosclerosis as well as hepatic steatosis without changing body weight gain in ApoE mice. Butyrate had metabolic effects on the liver by regulation of gene expression involved in lipid/glucose metabolism. Furthermore, ABCA1 was significantly induced by butyrate in vivo, ex vivo and in vitro and Sp1 pathway was identified as a potential mechanism.
Butyrate ameliorates HFD-induced atherosclerosis in ApoE mice via ABCA1-mediated cholesterol efflux in macrophages, which suggesting a promising therapeutic strategy for protecting against atherosclerosis.
肠道微生物代谢产物丁酸与代谢性疾病的调节有关。丁酸在动脉粥样硬化中的作用机制尚不清楚。因此，本研究对丁酸给药16周后对高脂饮食喂养的载脂蛋白E（ApoE）小鼠的影响进行了探究。
通过盲肠内容物的16S rRNA基因测序分析肠道微生物群组成。使用ApoE小鼠模型在体内评估丁酸对动脉粥样硬化的影响。分析血清脂质和葡萄糖的生理变化，并通过肝脏转录组分析鉴定肝脏样本中差异表达的基因。通过蛋白质免疫印迹和免疫组织化学染色对参与逆向胆固醇转运的蛋白质进行定量。最后，在RAW 264.7细胞中进一步评估丁酸对ATP结合盒亚家族A成员1（ABCA1）的上调作用以及特异性蛋白1的作用，通过抑制和沉默进行研究。
口服丁酸改变了微生物群组成，增强了高脂饮食（HFD）降低的肠道微生物多样性。丁酸治疗显著抑制了HFD诱导的动脉粥样硬化以及肝脂肪变性，而不改变ApoE小鼠的体重增加。丁酸通过调节参与脂质/葡萄糖代谢的基因表达对肝脏产生代谢作用。此外，丁酸在体内、体外和离体实验中均显著诱导ABCA1，并且Sp1途径被确定为潜在机制。
丁酸通过ABCA1介导的巨噬细胞胆固醇外流改善ApoE小鼠中HFD诱导的动脉粥样硬化，这提示了一种有前景的抗动脉粥样硬化治疗策略。
