|Title||Construction and Evaluation of an Organic Anion Transporter 1 (OAT1)-Centered Metabolic Network.|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Liu HC, Jamshidi N, Chen Y, Eraly SA, Cho SYee, Bhatnagar V, Wu W, Bush KT, Abagyan R, Palsson BO, Nigam SK|
|Journal||J Biol Chem|
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 Journal||J. Biol. Chem.|
Construction and Evaluation of an Organic Anion Transporter 1 (OAT1)-Centered Metabolic Network.