Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR‐PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria

Song, Min; Yang, Qiang; Zhang, Fenglin; Chen, Lin; Han, Seung-Beom; Yang, Xiaohua; He, Haiwen; Liu, Fangfang; Zheng, Jisong; Ling, Mingfa; Lai, Xumin; Zhu, Xiaotong; Wang, Lina; Gao, Ping; Shu, Gang; Jiang, Qingyan; Wang, Songbo

doi:10.1096/fj.201903244r

Cited by 48 publications

(39 citation statements)

References 54 publications

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“…In comparison with HFD group, the level of HDCA increased significantly and the β-MCA level decreased in HFD + AEE group. Previous study showed that HDCA altered BA metabolism profiles induced by gut bacteria ( Song et al, 2020 ). Meanwhile, it was found that HDCA was a candidate for anti-atherosclerotic drug therapy via increasing the ability of HDL ( Shih et al, 2013 ).…”

Section: Discussionmentioning

confidence: 96%

Untargeted and Targeted Metabolomics Reveal the Underlying Mechanism of Aspirin Eugenol Ester Ameliorating Rat Hyperlipidemia via Inhibiting FXR to Induce CYP7A1

Liu

et al. 2021

Front. Pharmacol.

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Hyperlipidemia is an important lipid disorder and a risk factor for health. Aspirin eugenol ester (AEE) is a novel synthetic compound which is made up of two chemical structural units from aspirin and eugenol. Therapeutic effect of AEE on hyperlipidemia has been confirmed in animal model. But the action mechanism of AEE on hyperlipidemia is still poorly understood. In this study, we investigated the effects of AEE on liver and feces metabolic profile through UPLC-Q-TOF/MS-based untargeted metabolomics in hyperlipidemia hamster induced with high fat diet (HFD), and the effects of AEE on the expression of genes and proteins related to cholesterol and bile acid (BA) in HFD-induced hyperlipidemia SD rat. The concentrations of 26 bile acids (BAs) in the liver from hyperlipidemia SD rat were also quantified with the application of BA targeted metabolomics. The results of untargeted metabolomics showed that the underlying mechanism of AEE on hyperlipidemia was mainly associated with amino acid metabolism, glutathione metabolism, energy metabolism, BA metabolism, and glycerophospholipid metabolism. AEE induced the expression of the BA-synthetic enzymes cholesterol 7α-hydroxylase (CYP7A1) by the inhibition of BA nuclear receptor farnesoid X receptor (FXR) in liver, which resulted in accelerating the conversion of cholesterol into bile acids and excrete in feces. The results of BA targeted metabolomics showed that AEE elevated the glycine-conjugated BA level and decreased the tauro-conjugated BA level. In conclusion, this study found that AEE decreased FXR and increased CYP7A1 in the liver, which might be the possible molecular mechanisms and targets of AEE for anti-hyperlipidemia therapies.

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Section: Discussionmentioning

confidence: 96%

Untargeted and Targeted Metabolomics Reveal the Underlying Mechanism of Aspirin Eugenol Ester Ameliorating Rat Hyperlipidemia via Inhibiting FXR to Induce CYP7A1

Liu

et al. 2021

Front. Pharmacol.

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“…In the ileum, we noted that an increase in the expression of ASBT and FXR after supplementing BA. Exogenous BA supplementation resulted in increases of several BA species, namely TUDCA, HDCA, and THDCA in the ileum, which can also function as a weak FXR agonist ( 58 ). However, the conflicting results of FXR induce ASBT expression in mice and inhibit ASBT expression in rabbits but do not affect ASBT in humans ( 59 ).…”

Section: Discussionmentioning

confidence: 99%

The Effect of Exogenous Bile Acids on Antioxidant Status and Gut Microbiota in Heat-Stressed Broiler Chickens

et al. 2021

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Bile acids are critical for lipid absorption, however, their new roles in maintaining or regulating systemic metabolism are irreplaceable. The negative impacts of heat stress (HS) on growth performance, lipid metabolism, and antioxidant status have been reported, but it remains unknown whether the bile acids (BA) composition of broiler chickens can be affected by HS. Therefore, this study aimed to investigate the modulating effects of the environment (HS) and whether dietary BA supplementation can benefit heat-stressed broiler chickens. A total of 216 Arbor Acres broilers were selected with a bodyweight approach average and treated with thermal neutral (TN), HS (32°C), or HS-BA (200 mg/kg BA supplementation) from 21 to 42 days. The results showed that an increase in average daily gain (P < 0.05) while GSH-Px activities (P < 0.05) in both serum and liver were restored to the normal range were observed in the HS-BA group. HS caused a drop in the primary BA (P = 0.084, 38.46%) and Tauro-conjugated BA (33.49%) in the ileum, meanwhile, the secondary BA in the liver and cecum were lower by 36.88 and 39.45% respectively. Notably, results were consistent that SBA levels were significantly increased in the serum (3-fold, P = 0.0003) and the ileum (24.89-fold, P < 0.0001). Among them, TUDCA levels (P < 0.01) were included. Besides, BA supplementation indeed increased significantly TUDCA (P = 0.0154) and THDCA (P = 0.0003) levels in the liver, while ileal TDCA (P = 0.0307), TLCA (P = 0.0453), HDCA (P = 0.0018), and THDCA (P = 0.0002) levels were also increased. Intestinal morphology of ileum was observed by hematoxylin and eosin (H&E) staining, birds fed with BA supplementation reduced (P = 0.0431) crypt depth, and the ratio of villous height to crypt depth trended higher (P = 0.0539) under the heat exposure. Quantitative RT-PCR showed that dietary supplementation with BA resulted in upregulation of FXR (P = 0.0369), ASBT (P = 0.0154), and Keap-1 (P = 0.0104) while downregulation of iNOS (P = 0.0399) expression in ileum. Moreover, 16S rRNA gene sequencing analysis and relevance networks revealed that HS-derived changes in gut microbiota and BA metabolites of broilers may affect their resistance to HS. Thus, BA supplementation can benefit broiler chickens during high ambient temperatures, serving as a new nutritional strategy against heat stress.

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“…Formononetin (FMNT), a isoflavonoid, possesses anti-inflammatory, antioxidant, and antitumoral properties (44)(45)(46), and supplementation of isoflavonoids can reduce the incidence and mortality of cancers (47,48). Hyodeoxycholic acid (HDCA) can suppress intestinal epithelial cell proliferation through the FXR-PI3K/AKT pathway (49). The reduced levels of lysophosphatidylethanolamine (LPEs), key components of cellular membranes, can explain the rapid cellular proliferation of malignancies (50).…”

Section: Discussionmentioning

confidence: 99%

Serum Metabolomic Profiling Reveals Biomarkers for Early Detection and Prognosis of Esophageal Squamous Cell Carcinoma

et al. 2022

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Esophageal squamous cell carcinoma (ESCC) is one of the most common aggressive malignancies worldwide, particularly in northern China. The absence of specific early symptoms and biomarkers leads to late-stage diagnosis, while early diagnosis and risk stratification are crucial for improving overall prognosis. We performed UPLC-MS/MS on 450 ESCC patients and 588 controls consisting of a discovery group and two validation groups to identify biomarkers for early detection and prognosis. Bioinformatics and clinical statistical methods were used for profiling metabolites and evaluating potential biomarkers. A total of 105 differential metabolites were identified as reliable biomarker candidates for ESCC with the same tendency in three cohorts, mainly including amino acids and fatty acyls. A predictive model of 15 metabolites [all-trans-13,14-dihydroretinol, (±)-myristylcarnitine, (2S,3S)-3-methylphenylalanine, 3-(pyrazol-1-yl)-L-alanine, carnitine C10:1, carnitine C10:1 isomer1, carnitine C14-OH, carnitine C16:2-OH, carnitine C9:1, formononetin, hyodeoxycholic acid, indole-3-carboxylic acid, PysoPE 20:3, PysoPE 20:3(2n isomer1), and resolvin E1] was developed by logistic regression after LASSO and random forest analysis. This model held high predictive accuracies on distinguishing ESCC from controls in the discovery and validation groups (accuracies > 89%). In addition, the levels of four downregulated metabolites [hyodeoxycholic acid, (2S,3S)-3-methylphenylalanine, carnitine C9:1, and indole-3-carboxylic acid] were significantly higher in early cancer than advanced cancer. Furthermore, three independent prognostic markers were identified by multivariate Cox regression analyses with and without clinical indicators: a high level of MG(20:4)isomer and low levels of 9,12-octadecadienoic acid and L-isoleucine correlated with an unfavorable prognosis; the risk score based on these three metabolites was able to stratify patients into low or high risk. Moreover, pathway analysis indicated that retinol metabolism and linoleic acid metabolism were prominent perturbed pathways in ESCC. In conclusion, metabolic profiling revealed that perturbed amino acids and lipid metabolism were crucial metabolic signatures of ESCC. Both panels of diagnostic and prognostic markers showed excellent predictive performances. Targeting retinol and linoleic acid metabolism pathways may be new promising mechanism-based therapeutic approaches. Thus, this study would provide novel insights for the early detection and risk stratification for the clinical management of ESCC and potentially improve the outcomes of ESCC.

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Hyodeoxycholic acid (HDCA) suppresses intestinal epithelial cell proliferation through FXR‐PI3K/AKT pathway, accompanied by alteration of bile acids metabolism profiles induced by gut bacteria

Cited by 48 publications

References 54 publications

Untargeted and Targeted Metabolomics Reveal the Underlying Mechanism of Aspirin Eugenol Ester Ameliorating Rat Hyperlipidemia via Inhibiting FXR to Induce CYP7A1

Untargeted and Targeted Metabolomics Reveal the Underlying Mechanism of Aspirin Eugenol Ester Ameliorating Rat Hyperlipidemia via Inhibiting FXR to Induce CYP7A1

The Effect of Exogenous Bile Acids on Antioxidant Status and Gut Microbiota in Heat-Stressed Broiler Chickens

Serum Metabolomic Profiling Reveals Biomarkers for Early Detection and Prognosis of Esophageal Squamous Cell Carcinoma

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