Integrative systems analysis identifies genetic and dietary modulators of bile acid homeostasis

Li, Hao; Perino, Alessia; Huang, Qingyao; Alvensleben, Giacomo von; Banaei‐Esfahani, Amir; Velázquez-Villegas, Laura A.; Gariani, Karim; Korbelius, Melanie; Sleiman, Maroun Bou; Imbach, Jéromine; Sun, Yu; Li, Xiaoxu; Bachmann, Alexis; Goeminne, Ludger; Gallart-Ayala, Héctor; Williams, Evan G.; Ivanišević, Julijana; Auwerx, Johan; Schoonjans, Kristina

doi:10.1016/j.cmet.2022.08.015

Cited by 20 publications

(12 citation statements)

References 81 publications

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“…In addition, we found that the application of new statistical and research methods to the existing results could identify signaling pathways more clearly, predict patient outcomes, and explore therapeutic targets with greater accuracy ( 46 , 47 ). Compared with the traditional gene-centered methods, this method based on the concept of network markers can better detect the signal nodes and axes interconnecting many differentially expressed genes, and thus provide higher prediction accuracy ( 47 ).…”

Section: Discussionmentioning

confidence: 99%

ENO1 contributes to 5-fluorouracil resistance in colorectal cancer cells via EMT pathway

Zhong

Wang

et al. 2022

Front. Oncol.

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IntroductionChemoresistance is a major barrier in the treatment of colorectal cancer (CRC) and many other cancers. ENO1 has been associated with various biological characteristics of CRC. This study aimed to investigate the function of ENO1 in regulating 5-Fluorouracil (5-FU) resistance in CRC.MethodsENO1 level in 120 pairs of tumor tissues and adjacent normal tissues was examined by immunohistochemistry, and the correlation between ENO1 expression and prognosis was explored by survival analysis. Its role and potential mechanisms in regulating 5-FU resistance in CRC were studied by Western blotting, MTT assay, colony formation assay and transwell invasion assay. Murine xenograft assay was implied to verify the results in vivo.ResultsOur study indicated that ENO1 was elevated in CRC tissues and was associated with poor patient prognosis. High levels of ENO1 expression were detected as a significant influencing factor for overall survival. Furthermore, ENO1 expression was found to have increased in drug-resistant cells (HCT116/5-FU and SW620/5-FU) constructed by increasing concentrations of 5-FU. Knockdown of ENO1 markedly increased the drug susceptibility and inhibited the proliferation and migration ability of HCT116/5-FU and SW620/5-FU cells. It was found that down-regulation of ENO1 inhibited the epithelial-mesenchymal transformation (EMT) signaling process. Finally, a murine xenograft assay verified that the depletion of ENO1 alleviated 5-FU resistance.ConclusionThis study identified that ENO1 regulated 5-FU resistance via the EMT pathway and may be a novel target in the prevention and treatment of 5-FUresistant CRC.

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Section: Discussionmentioning

confidence: 99%

ENO1 contributes to 5-fluorouracil resistance in colorectal cancer cells via EMT pathway

Zhong

Wang

et al. 2022

Front. Oncol.

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“…Given the microbial modification of BAs, the accumulation of primary BAs and the reduction of secondary BAs may be a consequence of HFD-mediated reduction in gut microbial diversity. [31] Altogether, these results reflected that HFD significantly altered colonic BA composition and abundance.…”

Section: High-fat Diet Increased the Abundance Of Primary Bas But Dec...mentioning

confidence: 76%

Bile Acid Derivatives Effectively Prevented High‐Fat Diet‐Induced Colonic Barrier Dysfunction

Shan

Huang

et al. 2023

Molecular Nutrition Food Res

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Scope: Bile acids (BAs) have recently emerged as important regulators of many physiological and pathological processes. However, the change of colonic BAs induced by high-fat diet (HFD) and their effects on colonic barrier function remain to be further elucidated. Methods and results: C57BL/6 mice are divided into two groups and feed 12 weeks with diets differing for fat content. Higher levels of serum diamine oxidase (DAO) activity, endotoxin (ET), and d-lactate (d-LA) are observed in HFD-fed mice, indicating an increase in intestinal permeability. Real-time quantitative PCR and western blot analyses demonstrate that HFD downregulates tight junction proteins (TJs, including zonula-occludens 1 [ZO-1], Occludin, and Claudin1) and Muc2 expression in the colon. The colonic BA profiles are analyzed by ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). HFD induces an increase in primary BAs but a decrease in secondary BAs. In human colonic cell line Caco-2, secondary BAs (deoxycholic acid [DCA], lithocholic acid [LCA], their 3-oxo-and iso-derivates) upregulate the expression of TJs and counteract DSS-induced increase in intestinal permeability at physiological concentrations. IsoDCA and isoLCA are the most effective ones. Moreover, supplementation of isoDCA or isoLCA also effectively prevents HFD-induced colonic barrier dysfunction in mice. Conclusion: These results demonstrate that secondary BAs (especially isomerized derivatives) may be important protectors for the colonic barrier function.

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“…For example, activated FXR is able to repress hepatic DNL 375 and gluconeogenesis 376 by inhibiting the expression of SREBP1c, PEPCK, and G6Pase. Moreover, systematic knockout of TGR5 could aggravate IR and glucose intolerance through miR‐26a and the subsequent cAMP/PKA pathway 377,378 . Furthermore, both FXR and TGR5 are capable to regulate GSIS in pancreatic β cells through inducing the relocalization of GLUT2 on the membrane 379 …”

Section: Signaling Pathways In T2dmmentioning

confidence: 99%

“…Moreover, systematic knockout of TGR5 could aggravate IR and glucose intolerance through miR-26a and the subsequent cAMP/PKA pathway. 377,378 Furthermore, both FXR and TGR5 are capable to regulate GSIS in pancreatic β cells through inducing the relocalization of GLUT2 on the membrane. 379 TGR5 is coexpressed with FXR on L cells in the intestine, and the activation of FXR could facilitate the release of GLP-1, 380 which then enhances insulin secretion and improves glucose homeostasis.…”

Section: Bile Acidsmentioning

confidence: 99%

Signaling pathways and intervention for therapy of type 2 diabetes mellitus

Cao

Tian

Zhang

et al. 2023

MedComm

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Type 2 diabetes mellitus (T2DM) represents one of the fastest growing epidemic metabolic disorders worldwide and is a strong contributor for a broad range of comorbidities, including vascular, visual, neurological, kidney, and liver diseases. Moreover, recent data suggest a mutual interplay between T2DM and Corona Virus Disease 2019 (COVID‐19). T2DM is characterized by insulin resistance (IR) and pancreatic β cell dysfunction. Pioneering discoveries throughout the past few decades have established notable links between signaling pathways and T2DM pathogenesis and therapy. Importantly, a number of signaling pathways substantially control the advancement of core pathological changes in T2DM, including IR and β cell dysfunction, as well as additional pathogenic disturbances. Accordingly, an improved understanding of these signaling pathways sheds light on tractable targets and strategies for developing and repurposing critical therapies to treat T2DM and its complications. In this review, we provide a brief overview of the history of T2DM and signaling pathways, and offer a systematic update on the role and mechanism of key signaling pathways underlying the onset, development, and progression of T2DM. In this content, we also summarize current therapeutic drugs/agents associated with signaling pathways for the treatment of T2DM and its complications, and discuss some implications and directions to the future of this field.

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Integrative systems analysis identifies genetic and dietary modulators of bile acid homeostasis

Cited by 20 publications

References 81 publications

ENO1 contributes to 5-fluorouracil resistance in colorectal cancer cells via EMT pathway

ENO1 contributes to 5-fluorouracil resistance in colorectal cancer cells via EMT pathway

Bile Acid Derivatives Effectively Prevented High‐Fat Diet‐Induced Colonic Barrier Dysfunction

Signaling pathways and intervention for therapy of type 2 diabetes mellitus

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