Nuclear Receptor Metabolism of Bile Acids and Xenobiotics: A Coordinated Detoxification System with Impact on Health and Diseases

Garcia, Manon; Thirouard, Laura; Sédes, Lauriane; Monrose, Mélusine; Holota, Hélène; Caira, Françoise; Volle, David H.; Beaudoin, Claude

doi:10.3390/ijms19113630

Cited by 34 publications

(25 citation statements)

References 169 publications

(195 reference statements)

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“…Furthermore, it could potentially allow for analysis of their connections to intermediary enzymes, such as the drug metabolizing enzymes (DMEs) as well as mechanisms regulating the expression of these genes in health and disease, such as those involving nuclear receptors. Indeed, many endogenous ligands are shared between subsets of SLC and ABC “drug” transporters, DMEs, and nuclear receptors (e.g., bile acids, fatty acids) 23,24 .…”

Section: Introductionmentioning

confidence: 99%

A Network of SLC and ABC Transporter and DME Genes Involved in Remote Sensing and Signaling in the Gut-Liver-Kidney Axis

Rosenthal

Bush

Nigám

2019

Sci Rep

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Genes central to drug absorption, distribution, metabolism and elimination (ADME) also regulate numerous endogenous molecules. The Remote Sensing and Signaling Hypothesis argues that an ADME gene-centered network—including SLC and ABC “drug” transporters, “drug” metabolizing enzymes (DMEs), and regulatory genes—is essential for inter-organ communication via metabolites, signaling molecules, antioxidants, gut microbiome products, uremic solutes, and uremic toxins. By cross-tissue co-expression network analysis, the gut, liver, and kidney (GLK) formed highly connected tissue-specific clusters of SLC transporters, ABC transporters, and DMEs. SLC22, SLC25 and SLC35 families were network hubs, having more inter-organ and intra-organ connections than other families. Analysis of the GLK network revealed key physiological pathways (e.g., involving bile acids and uric acid). A search for additional genes interacting with the network identified HNF4α, HNF1α, and PXR. Knockout gene expression data confirmed ~60–70% of predictions of ADME gene regulation by these transcription factors. Using the GLK network and known ADME genes, we built a tentative gut-liver-kidney “remote sensing and signaling network” consisting of SLC and ABC transporters, as well as DMEs and regulatory proteins. Together with protein-protein interactions to prioritize likely functional connections, this network suggests how multi-specificity combines with oligo-specificity and mono-specificity to regulate homeostasis of numerous endogenous small molecules.

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Section: Introductionmentioning

confidence: 99%

A Network of SLC and ABC Transporter and DME Genes Involved in Remote Sensing and Signaling in the Gut-Liver-Kidney Axis

Rosenthal

Bush

Nigám

2019

Sci Rep

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“…Bile acid metabolism requires coordinated activities of enzymes located in mitochondria, peroxisomes, ER, and the gut microbiome 45 . Bile acids are signaling molecules that bind to several classes of nuclear receptors (FXR, PXR, and CAR), and permit real-time coordination between food intake, the microbiome, liver, and systemic detoxification systems 46 . Bile acids are made from cholesterol and represent the major disposal route for excess cholesterol.…”

Section: Bile Acidsmentioning

confidence: 99%

Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence

Mocking

Naviaux

et al. 2021

Transl Psychiatry

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Recurrent major depressive disorder (rMDD) is a relapsing-remitting disease with high morbidity and a 5-year risk of recurrence of up to 80%. This was a prospective pilot study to examine the potential diagnostic and prognostic value of targeted plasma metabolomics in the care of patients with rMDD in remission. We used an established LC-MS/MS platform to measure 399 metabolites in 68 subjects with rMDD (n = 45 females and 23 males) in antidepressant-free remission and 59 age- and sex-matched controls (n = 40 females and 19 males). Patients were then followed prospectively for 2.5 years. Metabolomics explained up to 43% of the phenotypic variance. The strongest biomarkers were gender specific. 80% of the metabolic predictors of recurrence in both males and females belonged to 6 pathways: (1) phospholipids, (2) sphingomyelins, (3) glycosphingolipids, (4) eicosanoids, (5) microbiome, and (6) purines. These changes traced to altered mitochondrial regulation of cellular redox, signaling, energy, and lipid metabolism. Metabolomics identified a chemical endophenotype that could be used to stratify rrMDD patients at greatest risk for recurrence with an accuracy over 0.90 (95%CI = 0.69–1.0). Power calculations suggest that a validation study of at least 198 females and 198 males (99 cases and 99 controls each) will be needed to confirm these results. Although a small study, these results are the first to show the potential utility of metabolomics in assisting with the important clinical challenge of prospectively identifying the patients at greatest risk of recurrence of a depressive episode and those who are at lower risk.

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“…Bile acids start from the catabolism of cholesterol and are the nal product of cholesterol catabolism; they play a critical role in food digestion and nutrient absorption, helping the absorption of lipids and fat-soluble vitamins in the intestine [32,[34][35][36]. After passing down the intestine with bile, approximately 95% of bile acids are reabsorbed in the terminal ileum and circulate back to the liver through the portal vein [29,35,37]. The performance of these functions of bile acid mainly depends on its enterohepatic circulation process, which is of great signi cance for nutrient absorption and distribution, metabolic regulation and homeostasis [29,35,[37][38][39].…”

Section: Discussionmentioning

confidence: 99%

“…After passing down the intestine with bile, approximately 95% of bile acids are reabsorbed in the terminal ileum and circulate back to the liver through the portal vein [29,35,37]. The performance of these functions of bile acid mainly depends on its enterohepatic circulation process, which is of great signi cance for nutrient absorption and distribution, metabolic regulation and homeostasis [29,35,[37][38][39]. The results of metabolite network analysis showed that three metabolites related to bile acid synthesis were signi cantly negatively correlated with RFI traits, which means that they were positively correlated with feed e ciency.…”

Section: Discussionmentioning

confidence: 99%

Using nontargeted LC-MS metabolomics to identify the association of biomarkers in pig feces with feed efficiency

Quan

et al. 2020

Preprint

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Background: Improving feed efficiency is economically and environmentally beneficial in the pig industry. A deeper understanding of feed efficiency is essential on many levels for its highly complex nature. The aim of this project is to explore the relationship between fecal metabolites and feed efficiency-related traits, thereby identifying metabolites that may assist in the screening of the feed efficiency of pigs.Result: We performed fecal metabolomics analysis on 50 individuals selected from 225 Duroc x (Landrace x Yorkshire) (DLY) commercial pigs, 25 with an extremely high feed efficiency and 25 with an extremely low feed efficiency. A total of 6,749 and 5,644 m/z features were detected in positive and negative ionization modes by liquid chromatography-mass spectrometry (LC/MS). Through weighted coexpression network analysis (WGCNA), we found that one module in each positive and negative mode was related to residual feed intake (RFI), and six and three metabolites were further identified. The nine metabolites were found to be involved in multiple metabolic pathways, including lipid metabolism (primary bile acid synthesis, linoleic acid metabolism), vitamin D, glucose metabolism, and others. In parallel, the expression patterns of seven genes involved in lipid metabolism were illuminated by real-time qPCR. Then, Lasso regression analysis was used to evaluate the importance of nine metabolites obtained by the annotation process.Conclusions: Altogether, this study can not only provide new insights for the subsequent evaluation of commercial pig feed efficiency through small molecule metabolites, but also provide a reference for the development of new feed additives.

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Nuclear Receptor Metabolism of Bile Acids and Xenobiotics: A Coordinated Detoxification System with Impact on Health and Diseases

Cited by 34 publications

References 169 publications

A Network of SLC and ABC Transporter and DME Genes Involved in Remote Sensing and Signaling in the Gut-Liver-Kidney Axis

A Network of SLC and ABC Transporter and DME Genes Involved in Remote Sensing and Signaling in the Gut-Liver-Kidney Axis

Metabolic features of recurrent major depressive disorder in remission, and the risk of future recurrence

Using nontargeted LC-MS metabolomics to identify the association of biomarkers in pig feces with feed efficiency

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