PARP-1 inhibitor alleviates liver lipid accumulation of atherosclerosis via modulating bile acid metabolism and gut microbes†

IF 3 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Molecular omics Pub Date : 2023-05-10 DOI:10.1039/D3MO00033H
Yingkun Sheng, Guibing Meng, Zhirong Zhou, Ruijiao Du, Yuefei Wang and Miaomiao Jiang
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引用次数: 0

Abstract

Background: The DNA damage repair enzyme, poly(ADP-ribose) polymerase 1 (PARP1), is crucial for lipid and glucose metabolism. However, no evidence has been presented on the relationship between liver lipid accumulation and the PARP1 inhibitor, 3-aminobenzamide (3-AB), in atherosclerosis. Methods: ApoE−/− mice were used to explore the effect of 3-AB on atherosclerotic liver lipid accumulation, and the experiment of Sprague Dawley (SD) rats was designed to determine if the lowering of liver lipid levels by 3-AB was linked to gut bacteria. The levels of bile acid metabolism-related targets were assessed by ELISA, western blotting, and RT-qPCR. The relative abundances of gut microbes and biomarkers were determined using 16S rRNA sequencing analysis. Bile acid levels in the liver and ileum were examined by ultra-performance liquid chromatography-tandem mass spectrometry. The relationship between gut microbes and bile acids was assessed by Spearman's correlation analysis. Results: 3-AB significantly reduced the formation of aortic plaques in apoE−/− mice, according to gross oil red staining. H & E and Oil Red O staining revealed that 3-AB significantly reduced the hepatic lipid droplet area in ApoE−/− mice and SD rats. Compared with the atherosclerosis (ATH) group, 3-AB dramatically decreased the levels of total cholesterol (TC), triglyceride (TG), and low-density lipoprotein-cholesterol (LDL-C) in the serum of SD rats and apoE−/− mice, and the levels of TC, TG, and LDL-C in the serum and liver of apoE−/− mice. Furthermore, in apoE−/− mice and SD rats, 3-AB increased the mRNA and protein levels of farnesoid X receptor (FXR) and bile salt export pump (BSEP) in the liver, while inhibiting the mRNA and protein levels of FXR and fibroblast growth factor 15 (FGF15) in the ileum, respectively. 3-AB clearly inhibited the mRNA and protein levels of PARP1 in the liver and ileum of apoE−/− mice and rats. Following treatment with 3-AB, the levels of conjugated bile acids decreased in the liver of apoE−/− mice and increased in the ileum of SD rats, according to targeted metabolomic analysis. Microbiome sequencing analysis revealed that 3-AB reduced the relative abundance of Lactobacillus, Bifidobacterium, Listeria, Clostridium, Bacillus, and Staphylococcus in the feces of apoE−/− mice, and the relative abundance of Blautia, Clostridium, and Listeria in the feces of SD rats, eventually decreasing the total abundance of 10 bile salt hydrolase-associated gut microbes. According to the correlation analysis, 3-AB regulates bile acid metabolism, which is primarily related to Bifidobacterium. Conclusion: 3-AB alleviated atherosclerosis by modulating the bile acid metabolism and bile salt hydrolase-related gut microbes.

Abstract Image

PARP-1抑制剂通过调节胆汁酸代谢和肠道微生物†减轻动脉粥样硬化肝脂质积累
背景:DNA损伤修复酶聚(adp -核糖)聚合酶1 (PARP1)对脂质和葡萄糖代谢至关重要。然而,没有证据表明肝脂质积累与PARP1抑制剂3-氨基苯甲酰胺(3-AB)在动脉粥样硬化中的关系。方法:采用ApoE - / -小鼠研究3-AB对动脉粥样硬化性肝脏脂质积累的影响,并设计SD大鼠实验,确定3-AB对肝脏脂质水平的降低是否与肠道细菌有关。采用ELISA、western blotting和RT-qPCR检测胆汁酸代谢相关靶点的水平。采用16S rRNA测序分析确定肠道微生物和生物标志物的相对丰度。采用超高效液相色谱-串联质谱法检测肝脏和回肠胆汁酸水平。采用Spearman相关分析评估肠道微生物与胆汁酸之间的关系。结果:根据粗油红染色,3-AB显著减少apoE−/−小鼠主动脉斑块的形成。H,E和油红O染色显示,3-AB显著减少ApoE−/−小鼠和SD大鼠的肝脂滴面积。与动脉粥样硬化(ATH)组相比,3-AB显著降低SD大鼠和apoE - / -小鼠血清中总胆固醇(TC)、甘油三酯(TG)和低密度脂蛋白胆固醇(LDL-C)水平,降低apoE - / -小鼠血清和肝脏中TC、TG和LDL-C水平。此外,在apoE−/−小鼠和SD大鼠中,3-AB增加了肝脏中farnesoid X受体(FXR)和胆汁盐输出泵(BSEP)的mRNA和蛋白水平,同时抑制了回肠中FXR和成纤维细胞生长因子15 (FGF15)的mRNA和蛋白水平。3-AB明显抑制apoE−/−小鼠和大鼠肝脏和回肠中PARP1 mRNA和蛋白水平。根据靶向代谢组学分析,用3-AB治疗后,apoE - / -小鼠肝脏中的共轭胆汁酸水平下降,SD大鼠回肠中的共轭胆汁酸水平升高。微生物组测序分析显示,3-AB降低了apoE−/−小鼠粪便中乳酸杆菌、双歧杆菌、李斯特菌、梭菌、芽孢杆菌和葡萄球菌的相对丰度,以及SD大鼠粪便中Blautia、Clostridium和Listeria的相对丰度,最终降低了10种胆汁盐水解酶相关肠道微生物的总丰度。根据相关性分析,3-AB调节胆汁酸代谢,主要与双歧杆菌有关。结论:3-AB通过调节胆汁酸代谢和胆盐水解酶相关肠道微生物来缓解动脉粥样硬化。
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来源期刊
Molecular omics
Molecular omics Biochemistry, Genetics and Molecular Biology-Biochemistry
CiteScore
5.40
自引率
3.40%
发文量
91
期刊介绍: Molecular Omics publishes high-quality research from across the -omics sciences. Topics include, but are not limited to: -omics studies to gain mechanistic insight into biological processes – for example, determining the mode of action of a drug or the basis of a particular phenotype, such as drought tolerance -omics studies for clinical applications with validation, such as finding biomarkers for diagnostics or potential new drug targets -omics studies looking at the sub-cellular make-up of cells – for example, the subcellular localisation of certain proteins or post-translational modifications or new imaging techniques -studies presenting new methods and tools to support omics studies, including new spectroscopic/chromatographic techniques, chip-based/array technologies and new classification/data analysis techniques. New methods should be proven and demonstrate an advance in the field. Molecular Omics only accepts articles of high importance and interest that provide significant new insight into important chemical or biological problems. This could be fundamental research that significantly increases understanding or research that demonstrates clear functional benefits. Papers reporting new results that could be routinely predicted, do not show a significant improvement over known research, or are of interest only to the specialist in the area are not suitable for publication in Molecular Omics.
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