Xanthine oxidase inhibitor urate-lowering therapy titration to target decreases serum free fatty acids in gout and suppresses lipolysis by adipocytes

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Abstract

Objective

Linked metabolic and cardiovascular comorbidities are prevalent in hyperuricemia and gout. For mechanistic insight into impact on inflammatory processes and cardiometabolic risk factors of xanthine oxidase inhibitor urate-lowering therapy (ULT) titration to target, we performed a prospective study of gout serum metabolomes from a ULT trial.

Methods

Sera of gout patients meeting the 2015 ACR/EULAR gout classification criteria ( n = 20) and with hyperuricemia were studied at time zero and weeks 12 and 24 of febuxostat or allopurinol dose titration ULT. Ultrahigh performance liquid chromatography-tandem mass spectroscopy acquired the serum spectra. Data were assessed using the Metabolon and Metaboloanalyst software. Lipolysis validation assays were done in febuxostat and/or colchicine-treated 3T3-L1 differentiated adipocytes.

Results

Serum urate decreased from time zero (8.21 ±1.139 SD) at weeks 12 (5.965 ± 1.734 SD) and 24 (5.655 ±1.763 SD). Top metabolites generated by changes in nucleotide and certain amino acid metabolism and polyamine pathways were enriched at 12 and 24 weeks ULT, respectively. Decreases in multiple fatty acid metabolites were observed at 24 weeks, linked with obesity. In cultured adipocytes, febuxostat significantly decreased while colchicine increased the lipolytic response to β-adrenergic-agonism or TNF.

Conclusion

Metabolomic profiles linked xanthine oxidase inhibitor-based ULT titration to target with reduced serum free fatty acids. In vitro validation studies revealed that febuxostat, but not colchicine, reduced lipolysis in cultured adipocytes. Since soluble urate, xanthine oxidase inhibitor treatment, and free fatty acids modulate inflammation, our findings suggest that by suppressing lipolysis, ULT could regulate inflammation in gout and comorbid metabolic and cardiovascular disease.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13075-022-02852-4.

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KEGG: new perspectives on genomes, pathways, diseases and drugs

Minoru Kanehisa, Miho Furumichi, Mao Tanabe … (2016)

KEGG (http://www.kegg.jp/ or http://www.genome.jp/kegg/) is an encyclopedia of genes and genomes. Assigning functional meanings to genes and genomes both at the molecular and higher levels is the primary objective of the KEGG database project. Molecular-level functions are stored in the KO (KEGG Orthology) database, where each KO is defined as a functional ortholog of genes and proteins. Higher-level functions are represented by networks of molecular interactions, reactions and relations in the forms of KEGG pathway maps, BRITE hierarchies and KEGG modules. In the past the KO database was developed for the purpose of defining nodes of molecular networks, but now the content has been expanded and the quality improved irrespective of whether or not the KOs appear in the three molecular network databases. The newly introduced addendum category of the GENES database is a collection of individual proteins whose functions are experimentally characterized and from which an increasing number of KOs are defined. Furthermore, the DISEASE and DRUG databases have been improved by systematic analysis of drug labels for better integration of diseases and drugs with the KEGG molecular networks. KEGG is moving towards becoming a comprehensive knowledge base for both functional interpretation and practical application of genomic information.

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MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis

Jasmine Chong, Othman Soufan, Carin Li … (2018)

Abstract We present a new update to MetaboAnalyst (version 4.0) for comprehensive metabolomic data analysis, interpretation, and integration with other omics data. Since the last major update in 2015, MetaboAnalyst has continued to evolve based on user feedback and technological advancements in the field. For this year's update, four new key features have been added to MetaboAnalyst 4.0, including: (1) real-time R command tracking and display coupled with the release of a companion MetaboAnalystR package; (2) a MS Peaks to Pathways module for prediction of pathway activity from untargeted mass spectral data using the mummichog algorithm; (3) a Biomarker Meta-analysis module for robust biomarker identification through the combination of multiple metabolomic datasets and (4) a Network Explorer module for integrative analysis of metabolomics, metagenomics, and/or transcriptomics data. The user interface of MetaboAnalyst 4.0 has been reengineered to provide a more modern look and feel, as well as to give more space and flexibility to introduce new functions. The underlying knowledgebases (compound libraries, metabolite sets, and metabolic pathways) have also been updated based on the latest data from the Human Metabolome Database (HMDB). A Docker image of MetaboAnalyst is also available to facilitate download and local installation of MetaboAnalyst. MetaboAnalyst 4.0 is freely available at http://metaboanalyst.ca.

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Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases

Jason Lloyd-Price, Cesar Arze, Ashwin Ananthakrishnan … (2019)

Inflammatory bowel diseases, which include Crohn’s disease and ulcerative colitis, affect several million individuals worldwide. Crohn’s disease and ulcerative colitis are complex diseases that are heterogeneous at the clinical, immunological, molecular, genetic, and microbial levels. Individual contributing factors have been the focus of extensive research. As part of the Integrative Human Microbiome Project (HMP2 or iHMP), we followed 132 subjects for one year each to generate integrated longitudinal molecular profiles of host and microbial activity during disease (up to 24 time points each; in total 2,965 stool, biopsy, and blood specimens). Here we present the results, which provide a comprehensive view of functional dysbiosis in the gut microbiome during inflammatory bowel disease activity. We demonstrate a characteristic increase in facultative anaerobes at the expense of obligate anaerobes, as well as molecular disruptions in microbial transcription (for example, among clostridia), metabolite pools (acylcarnitines, bile acids, and short-chain fatty acids), and levels of antibodies in host serum. Periods of disease activity were also marked by increases in temporal variability, with characteristic taxonomic, functional, and biochemical shifts. Finally, integrative analysis identified microbial, biochemical, and host factors central to this dysregulation. The study’s infrastructure resources, results, and data, which are available through the Inflammatory Bowel Disease Multi’omics Database (http://ibdmdb.org), provide the most comprehensive description to date of host and microbial activities in inflammatory bowel diseases.

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Author and article information

Contributors

Robert Terkeltaub:

ORCID: http://orcid.org/0000-0001-5368-7473

rterkeltaub@health.ucsd.edu

Journal

Journal ID (nlm-ta): Arthritis Res Ther

Journal ID (iso-abbrev): Arthritis Res Ther

Title: Arthritis Research & Therapy

Publisher: BioMed Central (London )

ISSN (Print): 1478-6354

ISSN (Electronic): 1478-6362

Publication date (Electronic): 25 July 2022

Publication date PMC-release: 25 July 2022

Publication date (Print): 2022

Volume: 24

Electronic Location Identifier: 175

Affiliations

[1 ]GRID grid.266100.3, ISNI 0000 0001 2107 4242, Department of Medicine, , UC San Diego, San Diego VA Healthcare Service, ; 3350 La Jolla Village Drive, San Diego, CA 92161 USA

[2 ]GRID grid.7080.f, ISNI 0000 0001 2296 0625, Department of Medicine, , Autonomous University of Barcelona, ; Plaça Cívica, 08193 Bellaterra, Barcelona Spain

[3 ]GRID grid.217200.6, ISNI 0000 0004 0627 2787, Division of Metabolism and Endocrinology, Department of Medicine, , University of California-San Diego, ; La Jolla, CA 92093 USA

[4 ]GRID grid.266813.8, ISNI 0000 0001 0666 4105, University of Nebraska Medical Center, ; Omaha, NE 68198 USA

[5 ]GRID grid.5386.8, ISNI 000000041936877X, Weill Center for Metabolic Health, Department of Medicine, , Weill Cornell Medicine, ; New York, NY 10021 USA

Author information

Robert Terkeltaub http://orcid.org/0000-0001-5368-7473

Article

Publisher ID: 2852

DOI: 10.1186/s13075-022-02852-4

PMC ID: 9310412

PubMed ID: 35879786

SO-VID: c446f46e-be88-4573-9301-456df85f0cd3

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 7 June 2021

Date accepted : 26 June 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: AR073324

Award ID: T32AR064194

Award ID: DK126944

Award ID: AR060772

Award ID: AR075990

Award Recipient : Monica Guma Roxana Coras Ru Liu-Bryan Robert Terkeltaub

Funded by: FundRef http://dx.doi.org/10.13039/100009012, Veterans Affairs San Diego Healthcare System;

Custom metadata

ScienceOpen disciplines: Orthopedics

Keywords: xanthine oxidase,lipolysis,metabolomics,gout,adipocytes,microbiome

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ScienceOpen disciplines: Orthopedics

Keywords: xanthine oxidase, lipolysis, metabolomics, gout, adipocytes, microbiome

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Xanthine oxidase inhibitor urate-lowering therapy titration to target decreases serum free fatty acids in gout and suppresses lipolysis by adipocytes

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Abstract

Objective

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Supplementary Information

Related collections

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Most cited references 61

KEGG: new perspectives on genomes, pathways, diseases and drugs

MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis

Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases

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