The organic anion transporter (OAT) subfamily, which constitutes roughly half of the SLC22 (solute carrier 22) transporter family, has received a great deal of attention because of its role in handling of common drugs (antibiotics, antivirals, diuretics, nonsteroidal anti-inflammatory drugs), toxins (mercury, aristolochic acid), and nutrients (vitamins, flavonoids). Oats are expressed in many tissues, including kidney, liver, choroid plexus, olfactory mucosa, brain, retina, and placenta. Recent metabolomics and microarray data from Oat1 [Slc22a6, originally identified as NKT (novel kidney transporter)] and Oat3 (Slc22a8) knockouts, as well as systems biology studies, indicate that this pathway plays a central role in the metabolism and handling of gut microbiome metabolites as well as putative uremic toxins of kidney disease. Nuclear receptors and other transcription factors, such as Hnf4α and Hnf1α, appear to regulate the expression of certain Oats in conjunction with phase I and phase II drug metabolizing enzymes. Some Oats have a strong selectivity for particular signaling molecules, including cyclic nucleotides, conjugated sex steroids, odorants, uric acid, and prostaglandins and/or their metabolites. According to the "Remote Sensing and Signaling Hypothesis," which is elaborated in detail here, Oats may function in remote interorgan communication by regulating levels of signaling molecules and key metabolites in tissues and body fluids. Oats may also play a major role in interorganismal communication (via movement of small molecules across the intestine, placental barrier, into breast milk, and volatile odorants into the urine). The role of various Oat isoforms in systems physiology appears quite complex, and their ramifications are discussed in the context of remote sensing and signaling.

There is an apparent overlap between areas in the USA where the herbicide, atrazine (ATZ), is heavily used and obesity-prevalence maps of people with a BMI over 30. Given that herbicides act on photosystem II of the thylakoid membrane of chloroplasts, which have a functional structure similar to mitochondria, we investigated whether chronic exposure to low concentrations of ATZ might cause obesity or insulin resistance by damaging mitochondrial function. Sprague-Dawley rats (n = 48) were treated for 5 months with low concentrations (30 or 300 µg kg−1 day−1) of ATZ provided in drinking water. One group of animals was fed a regular diet for the entire period, and another group of animals was fed a high-fat diet (40% fat) for 2 months after 3 months of regular diet. Various parameters of insulin resistance were measured. Morphology and functional activities of mitochondria were evaluated in tissues of ATZ-exposed animals and in isolated mitochondria. Chronic administration of ATZ decreased basal metabolic rate, and increased body weight, intra-abdominal fat and insulin resistance without changing food intake or physical activity level. A high-fat diet further exacerbated insulin resistance and obesity. Mitochondria in skeletal muscle and liver of ATZ-treated rats were swollen with disrupted cristae. ATZ blocked the activities of oxidative phosphorylation complexes I and III, resulting in decreased oxygen consumption. It also suppressed the insulin-mediated phosphorylation of Akt. These results suggest that long-term exposure to the herbicide ATZ might contribute to the development of insulin resistance and obesity, particularly where a high-fat diet is prevalent.

Organic anion transporters (Oats) are located in the barrier epithelia of diverse organs, where they mediate the absorption and excretion of a wide range of metabolites, signaling molecules, and xenobiotics. Although their interactions with a broad group of substrates have been extensively studied and described, the primary physiological role of Oats remains elusive. The presence of overlapping substrate specificities among the different Oat isoforms, together with recent metabolomic data from the Oat1, Oat3, and renal-specific transporter (RST/ URAT1) knockout mice, suggests a possible role in remote signaling wherein substrates excreted through one Oat isoform in one organ are taken up by another Oat isoform located in a different organ, thereby mediating communication between different organ systems, or even between different organisms.Here we further develop this "remote sensing and signaling hypothesis" and suggest how the regulation of SLC22 subfamily members (including those of the organic cation, organic carnitine, and unknown substrate transporter subfamilies) can be better understood by considering the organism's broader need to communicate between epithelial and other tissues by simultaneous regulation of transport of metabolites, signaling molecules, drugs, and toxins. This systems biology perspective of remote signaling (sensing) could help reconcile an enormous array of tissue-specific data for various SLC22 family genes and, possibly, other multispecific transporters, such as those of the organic anion transporting polypeptide (OATP, SLC21) and multidrug resistance-associated protein (MRP) families.

The main kidney transporter of many commonly prescribed drugs (e.g. penicillins, diuretics, antivirals, methotrexate, and non-steroidal anti-inflammatory drugs) is organic anion transporter-1 (OAT1), originally identified as NKT (Lopez-Nieto, C. E., You, G., Bush, K. T., Barros, E. J., Beier, D. R., and Nigam, S. K. (1997) J. Biol. Chem. 272, 6471-6478). Targeted metabolomics in knockouts have shown that OAT1 mediates the secretion or reabsorption of many important metabolites, including intermediates in carbohydrate, fatty acid, and amino acid metabolism. This observation raises the possibility that OAT1 helps regulate broader metabolic activities. We therefore examined the potential roles of OAT1 in metabolic pathways using Recon 1, a functionally tested genome-scale reconstruction of human metabolism. A computational approach was used to analyze in vivo metabolomic as well as transcriptomic data from wild-type and OAT1 knock-out animals, resulting in the implication of several metabolic pathways, including the citric acid cycle, polyamine, and fatty acid metabolism. Validation by in vitro and ex vivo analysis using Xenopus oocyte, cell culture, and kidney tissue assays demonstrated interactions between OAT1 and key intermediates in these metabolic pathways, including previously unknown substrates, such as polyamines (e.g. spermine and spermidine). A genome-scale metabolic network reconstruction generated some experimentally supported predictions for metabolic pathways linked to OAT1-related transport. The data support the possibility that the SLC22 and other families of transporters, known to be expressed in many tissues and primarily known for drug and toxin clearance, are integral to a number of endogenous pathways and may be involved in a larger remote sensing and signaling system The kidney is responsible for the elimination of toxic substances and wastes as well as for the reabsorption of 99% of the glomerular ultrafiltrate each day (ϳ60% of which occurs in the proximal tubule) (1). Among the transporters that drive this reabsorption and secretion process are the organic anion transporters (OATs), 3 which transport an extensive range of endogenous metabolites, such as tricarboxylic acid (TCA) cycle intermediates, cyclic nucleotides, and prostaglandins, and also serve as "drug/xenobiotic transporters" (2). Their abundance in a wide range of tissues other than the kidney, including tissues not generally considered to be sites of xenobiotic elimination, as well as their conservation down to fly and worm (3), indicates an important physiological role for these transporters. The OATs have been shown to mediate the transport of numerous endogenous/exogenous solutes, and a role in blood pressure regulation for OAT3 (4) and remote sensing for OAT6 (5) has been suggested. In addition, the highly active metabolic reactions that occur in the proximal tubule in order to fuel its extensive transport processes as well as the fact that the OATs transport many important metabolic intermediates suggest a vital role in th...

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