Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 292, Issue 38, Pages 15789-15803Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M117.796516
Keywords
-
Categories
Funding
- NICHD NIH HHS [U54 HD090259, P50 HD090259] Funding Source: Medline
- NIDDK NIH HHS [R01 DK109392] Funding Source: Medline
- NIGMS NIH HHS [R01 GM098449, R01 GM104098] Funding Source: Medline
Ask authors/readers for more resources
The organic anion transporters OAT1 (SLC22A6) and OAT3 (SLC22A8) have similar substrate specificity for drugs, but it is far from clear whether this holds for endogenous substrates. By analysis of more than 600 metabolites in the Oat3KO (Oat3 knockout) by LC/MS, we demonstrateOAT3involvement in the movement of gut microbiome products, key metabolites, and signaling molecules, including those flowing through the gutliver-kidney axis. Major pathways affected included those involved in metabolism of bile acids, flavonoids, nutrients, amino acids (including tryptophan-derivatives that are uremic toxins), and lipids. OAT3 is also critical in elimination of liverderived phase II metabolites, particularly those undergoing glucuronidation. Analysis of physicochemical features revealed nine distinct metabolite groups; at least one member of most clusters has been previously validated in transport assays. In contrast to drugs interacting with the OATs, endogenous metabolites accumulating in the Oat1KO (Oat1 knockout) versus Oat3KO have distinct differences in their physicochemical properties; they are very different in size, number of rings, hydrophobicity, and molecular complexity. Consistent with the Remote Sensing and Signaling Hypothesis, the data support the importance of the OAT transporters in inter-organ and interorganismal remote communication via transporter-mediated movement of key metabolites and signaling molecules (e. g. gut microbiome-to-intestine-to-blood-to-liver-to-kidney-tourine). We discuss the possibility of an intimate connection between OATs and metabolite sensing and signaling pathways (e. g. bile acids). Furthermore, the metabolomics and pathway analysis support the view that OAT1 plays a greater role in kidney proximal tubule metabolism and OAT3 appears relatively more important in systemic metabolism, modulating levels of metabolites flowing through intestine, liver, and kidney.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available