title: An Organic Anion Transporter 1 (OAT1)-centered Metabolic Network.
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 knock-out 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. 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, S. K. (2015) Nat. Rev. Drug Disc. 14, 29). The fact that OAT1 can affect many systemic biological pathways suggests that drug-metabolite interactions need to be considered beyond simple competition for the drug transporter itself and may explain aspects of drug-induced metabolic syndrome. Our approach should provide novel mechanistic insights into the role of OAT1 and other drug transporters implicated in metabolic diseases like gout, diabetes, and chronic kidney disease.
authors.affiliation: From the Departments of Bioengineering.
authors.forename: Henry C
authors.initials: HC
authors.lastname: Liu
authors.affiliation: From the Departments of Bioengineering.
authors.forename: Neema
authors.initials: N
authors.lastname: Jamshidi
authors.affiliation: Bioinformatics and Systems Biology Graduate Program.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Medicine.
authors.forename: Satish A
authors.initials: SA
authors.lastname: Eraly
authors.affiliation: Chemistry and Biochemistry.
authors.forename: Sai Yee
authors.initials: SY
authors.lastname: Cho
authors.affiliation: Family and Preventative Medicine.
authors.forename: Vibha
authors.initials: V
authors.lastname: Bhatnagar
authors.affiliation: Medicine.
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.affiliation: Pediatrics, and.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Bush
authors.affiliation: Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, California 92093.
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
authors.affiliation: From the Departments of Bioengineering.
authors.forename: Bernhard O
authors.initials: BO
authors.lastname: Palsson
authors.affiliation: Medicine, Pediatrics, and Cellular and Molecular Medicine, snigam@ucsd.edu.
authors.forename: Sanjay K
authors.initials: SK
authors.lastname: Nigam
mesh_terms: D000818:Animals; D055442:Metabolome / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism*
chemical_list: D027362:Organic Anion Transport Protein 1; C105033:Slc22a6 protein, mouse
keywords: ABC transporter; Recon; SLC transporter; chronic kidney disease; diabetes; genome-scale metabolic reconstruction; kidney; microbiome; pharmacophore; systems biology