Alisol B 23-acetate adjusts bile acid metabolisim via hepatic FXR-BSEP signaling activation to alleviate atherosclerosis

Fu, Y.; Han, Fang; Ding, Xue; Meng, Qingcai; Zhang, Shu-Rui; Li, Jun; Cao, Ying; Ji, Tingting; Bi, Yunhui; Zhang, Weiwei; Chen, Qi; Zhang, Yuhan; Fen, You-Long; Bian, Huimin

doi:10.1016/j.phymed.2022.154120

Cited by 23 publications

(17 citation statements)

References 50 publications

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“…Our qPCR results show that the mRNA expressions of FXR, BSEP , and SHP were increased with Rc treatment. This result is in accordance with those reported for FXR activating its downstream genes BSEP and SHP ( Wang et al, 2017 ; Fu et al, 2022 ). To our knowledge, this is first time that Rc has been reported as an FXR regulator.…”

Section: Discussionsupporting

confidence: 93%

Ginsenoside Rc attenuates DSS-induced ulcerative colitis, intestinal inflammatory, and barrier function by activating the farnesoid X receptor

et al. 2022

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Objectives: Farnesoid X receptor (FXR) activation is involved in ameliorating inflammatory bowel disease (IBD), such as ulcerative colitis (UC), and inflammatory regulation may be involved in its mechanism. Ginsenoside Rc (Rc) is a major component of Panax ginseng, and it plays an excellent role in the anti-inflammatory processes. Our aim is to explore the alleviative effect of Rc on dextran sulfate sodium (DSS)-induced inflammation and deficiencies in barrier function based on FXR signaling.Materials and Methods:In vitro, we treated human intestinal epithelial cell lines (LS174T) with LPS to explore the anti-inflammatory effect of Rc supplementation. In vivo, a DSS-induced IBD mice model was established, and the changes in inflammatory and barrier function in colons after Rc treatment were measured using the disease activity index (DAI), hematoxylin and eosin (H&E) staining, immunofluorescence, ELISA, and qPCR. Molecular docking analysis, luciferase reporter gene assay, and qPCR were then used to analyze the binding targets of Rc. DSS-induced FXR-knockout (FXR−/-) mice were used for further validation.Results: Rc significantly recovered the abnormal levels of inflammation indexes (TNF-α, IL-6, IL-1β, and NF-KB) induced by LPS in LS174T. DSS-induced C57BL/6 mice exhibited a significantly decreased body weight and elevated DAI, as well as a decrease in colon weight and length. Increased inflammatory markers (TNF-α, IL-6, IL-1β, ICAM1, NF-KB, F4/80, and CD11b displayed an increased expression) and damaged barrier function (Claudin-1, occludin, and ZO-1 displayed a decreased expression) were observed in DSS-induced C57BL/6 mice. Nevertheless, supplementation with Rc mitigated the increased inflammatory and damaged barrier function associated with DSS. Further evaluation revealed an activation of FXR signaling in Rc-treated LS174T, with FXR, BSEP, and SHP found to be upregulated. Furthermore, molecular docking indicated that there is a clear interaction between Rc and FXR, while Rc activated transcriptional expression of FXR in luciferase reporter gene assay. However, these reversal abilities of Rc were not observed in DSS-induced FXR−/- mice.Conclusion: Our findings suggest that Rc may ameliorate inflammation and barrier function in the intestine, which in turn leads to the attenuation of DSS-induced UC, in which Rc may potentially activate FXR signaling to protect the intestines from DSS-induced injury.

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Section: Discussionsupporting

confidence: 93%

Ginsenoside Rc attenuates DSS-induced ulcerative colitis, intestinal inflammatory, and barrier function by activating the farnesoid X receptor

et al. 2022

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“…In additional, we identified that glycine‐β‐muricholic acid (Gly‐MCA) acted as an antagonist which inhibited intestinal FXR, thereby altering the host's liver lipid metabolism and improving metabolic dysfunction (Zhang et al, 2016). In ovariectomized mice, increased levels of CDCA in the liver were found to activate hepatic FXR‐BSEP signaling and reduce atherosclerotic damage by decreased bile acid efflux (Fu et al, 2022). These suggested that bile acids are closely associated with the development of metabolic cardiovascular disease and may exert cardioprotective effects through anti‐inflammatory and lipid metabolism regulation.…”

Section: Discussionmentioning

confidence: 99%

Ethanol extract of Pueraria lobata improve acute myocardial infarction in rats via regulating gut microbiota and bile acid metabolism

Zhang,

Fang,

Zhao

et al. 2023

Phytotherapy Research

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Background and AimAcute myocardial infarction (AMI) is a multifactorial disease with high mortality rate worldwide. Ethanol extract of Pueraria lobata (EEPL) has been widely used in treating cardiovascular diseases in China. This study aimed to explore the underlying therapeutic mechanism of EEPL in AMI rats.Experimental ProcedureWe first evaluated the anti‐AMI efficacy of EEPL through immunohistochemistry staining and biochemical indexes. Then, UPLC‐MS/MS, 16S rDNA, and shotgun metagenomic sequencing were used to analyze the alterations in bile acid metabolism and intestinal flora. Finally, the influence of EEPL on ilem bile acid metabolism, related enzymes expression, and transporter proteins expression in rats were verified by mass spectrometry image and ELISA.Key ResultsThe results showed that EEPL can reduce cardiac impairment in AMI rats. Besides, EEPL effectively increased bile acid levels and regulated gut microbiota disturbance in AMI rats via increasing CYP7A1 expression and restoring intestinal microbiota diversity, separately. Moreover, it can increase bile acids reabsorption and fecal excretion through inhibiting FXR‐FGF15 signaling pathway and increasing OST‐α expression, which associated with Lachnoclostridium.Conclusions and ImplicationsOur findings demonstrated that EEPL alleviated AMI partially by remediating intestinal dysbiosis and promoting bile acid biosynthesis, which provided new targets for AMI treatment.

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“…In addition, bile acid metabolism is regulated by intestinal flora. Yu Fu’s research further elaborated that the metabolic pathway of liver cholesterol-bile acid can finally regulate liver cholesterol metabolism and alleviate abnormal lipid metabolism by influencing the abundance and species of intestinal flora [ 22 ]. In addition, Meng Qing directly explained that different intestinal bacteria, including Lactobacillus and Bifidobacterium , can alleviate AS in ApoE −/− mice fed with a high-cholesterol diet [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Excessive exogenous cholesterol activating intestinal LXRα-ABCA1/G5/G8 signaling pathway can not reverse atherosclerosis in ApoE−/− mice

Ding

Han

et al. 2023

Lipids Health Dis

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Background The long-term excessive intake of exogenous cholesterol can lead to abnormally elevated blood lipid levels and induce cardiovascular and cerebrovascular diseases. However, the influence and relevance of exogenous cholesterol on plasma cholesterol components were still unclear, and the influence on intestinal lipid metabolism targets needs to be further explored. Methods In vivo, the C57BL/6 + NF group and ApoE−/− + NF group mice were fed a normal specific pathogen-free (SPF) diet; the ApoE−/− + HF group mice were fed a high-cholesterol SPF diet. The plasma and jejunum tissue homogenate were obtained for non-targeted lipid metabolomics. The lipid droplets in tissues were observed by transmission electron microscope and oil red O staining. Jejunum tissue morphology was observed by HE staining. The kits were used to detect lipid content in plasma, tissues, intestinal contents, and cells. Western blot, RT-PCR, immunohistochemistry (IHC), and immunofluorescence (IF) were used to observe the key target of lipid metabolism. In vitro, the final concentration of cholesterol was 100 μmol/L in Caco-cells. Oil red O staining, western blot, RT-PCR and immunofluorescence (IF) were used to observe the changes of lipid metabolism. Finally, the influence of liver X receptor alpha (LXRα) on intestinal cholesterol metabolism was clarified by applying the LXRα inhibitor GSK2033 and siRNA targeting LXRα. Results The aortic arch and intestinal villi of the two groups of ApoE−/− mice showed apparent lesions and lipid accumulation, and there were significant changes in a variety of lipids in the plasma and jejunum. Additionally, jejunum LXRα was markedly activated. High cholesterol can significantly activate LXRα in Caco-2 cells. After LXRα was inhibited, the protein level of ATP-binding cassette transporter A1/G5/G8 (ABCA1/G5/G8) decreased, and the quantity and volume of intracellular lipids soared. Conclusion In a high-cholesterol environment, the intestine promotes the excretion of cholesterol from the cell through the LXRα-ABCA1/G5/G8 pathway, reduces the intestinal intake of a variety of exogenous cholesterol, and reduces the risk of AS. Graphical Abstract

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Alisol B 23-acetate adjusts bile acid metabolisim via hepatic FXR-BSEP signaling activation to alleviate atherosclerosis

Cited by 23 publications

References 50 publications

Ginsenoside Rc attenuates DSS-induced ulcerative colitis, intestinal inflammatory, and barrier function by activating the farnesoid X receptor

Ginsenoside Rc attenuates DSS-induced ulcerative colitis, intestinal inflammatory, and barrier function by activating the farnesoid X receptor

Ethanol extract of Pueraria lobata improve acute myocardial infarction in rats via regulating gut microbiota and bile acid metabolism

Excessive exogenous cholesterol activating intestinal LXRα-ABCA1/G5/G8 signaling pathway can not reverse atherosclerosis in ApoE−/− mice

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