Construction and Evaluation of an Organic Anion Transporter 1 (OAT1)-Centered Metabolic Network.

TitleConstruction and Evaluation of an Organic Anion Transporter 1 (OAT1)-Centered Metabolic Network.
Publication TypeJournal Article
Year of Publication2016
AuthorsLiu HC, Jamshidi N, Chen Y, Eraly SA, Cho SYee, Bhatnagar V, Wu W, Bush KT, Abagyan R, Palsson BO, Nigam SK
JournalJ Biol Chem
PubMed Date07/2016
ISSN1083-351X
Abstract

There has been a recent interest in the broader physiological importance of multispecific drug transporters of the SLC and ABC transporter families. Here, a novel multi-tiered systems biology approach was used to predict metabolites and signaling molecules potentially affected by the in vivo deletion of organic anion transporter 1 (Oat1, Slc22a6, originally NKT), a major kidney-expressed drug transporter. Validation of some predictions in wet-lab assays, together with re-evaluation of existing transport and knockout metabolomics data, generated an experimentally-validated, confidence-ranked set of OAT1-interacting endogenous compounds enabling construction of an OAT1-centered metabolic interaction network. Pathway and enrichment analysis indicated an important role for OAT1 in metabolism involving: the TCA cycle, tryptophan and other amino acids, fatty acids, prostaglandins, cyclic nucleotides, odorants, polyamines, and vitamins. The partly-validated reconstructed network is also consistent with a major role for OAT1 in modulating metabolic and signaling pathways involving uric acid, gut microbiome products and so-called uremic toxins accumulating in chronic kidney disease (CKD). Together, the findings are compatible with the hypothesized role of drug transporters in remote inter-organ and inter-organismal communication (the Remote Sensing and Signaling Hypothesis, Nigam SK. 2015, Nature Rev Drug Disc 14:29). The fact that OAT1 can affect many systemic biological pathways suggests that drug-metabolite interactions (DMI) need to be considered beyond simple competition for the drug transporter itself and may explain aspects of drug-induced metabolic syndromes. Our approach should provide novel mechanistic insights into the role of OAT1 and other drug transporters implicated in metabolic diseases like gout, diabetes and CKD.

Alternate JournalJ. Biol. Chem.
PubMed ID27440044
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