The SLC22 Transporter Family: A Paradigm for the Impact of Drug Transporters on Metabolic Pathways, Signaling, and Disease

Abstract

The SLC22 transporter family consists of more than two dozen members, which are expressed in the kidney, the liver, and other tissues. Evolutionary analysis indicates that SLC22 transporters fall into at least six subfamilies: OAT (organic anion transporter), OAT-like, OAT-related, OCT (organic cation transporter), OCTN (organic cation/carnitine transporter), and OCT/OCTN-related. Some-including OAT1 [SLC22A6 or NKT (novel kidney transporter)] and OAT3 (SLC22A8), as well as OCT1 (SLC22A1) and OCT2 (SLC22A2)-are widely studied drug transporters. Nevertheless, analyses of knockout mice and other data indicate that SLC22 transporters regulate key metabolic pathways and levels of signaling molecules (e.g., gut microbiome products, bile acids, tricarboxylic acid cycle intermediates, dietary flavonoids and other nutrients, prostaglandins, vitamins, short-chain fatty acids, urate, and ergothioneine), as well as uremic toxins associated with chronic kidney disease. Certain SLC22 transporters-such as URAT1 (SLC22A12) and OCTN2 (SLC22A5)-are mutated in inherited metabolic diseases. A new systems biology view of transporters is emerging. As proposed in the remote sensing and signaling hypothesis, SLC22 transporters, together with other SLC and ABC transporters, have key roles in interorgan and interorganism small-molecule communication and, together with the neuroendocrine, growth factor-cytokine, and other homeostatic systems, regulate local and whole-body homeostasis.

Weighted Gene Correlation Network Analysis (WGCNA) Detected Loss of MAGI2 Promotes Chronic Kidney Disease (CKD) by Podocyte Damage

“…Taking the brown module as an example, which showed functional enrichment in metabolic and oxidation-reduction processes, some hub genes have been also reported to participate in similar processes, e.g. the SLC13 Family (SLC13A3) [28,29], SLC22 Family (SLC22A6) [30] or MSRA that plays a protective role in the progression of UUO-induced kidney fibrosis via suppression of fibrotic responses caused by oxidative stress [31]. Similarly, some hub genes in the yellow module have been identified as pro-inflammatory factors in a variety of human diseases, including CTSS and ITGB2 [32], consistent with the BP term or KEGG pathway enriched in the yellow module.…”

The systems biology of uric acid transporters

“…Together, these studies provide a detailed in-vivo and in-vitro portrait of how SLC and ABC uric acid transporters, many of which are better known as multispecific ‘drug’ transporters, involved in absorption, distribution, and elimination of common organic anion drugs, work along with liver enzymes involved in purine metabolism, to regulate uric acid levels [11,18,19*,21]. Although many of these uric acid transporters are most highly expressed in the kidney, where they function in urate handling by the proximal tubule resulting in net renal excretion (Fig.…”

“…This hypothesis proposes that these SLC and ABC transporters, which are expressed in different tissues lining distinct body fluid compartments (including blood, urine, bile, CSF, and amniotic fluid), play an essential role in regulating interorgan and interorganismal (e.g., gut microbiome–host) communication by transporting key small molecule metabolites and signaling molecules throughout the body (Fig. 3) [11,17,18, 19*,21]. The remote sensing and signaling system is thus envisioned to be a communication network of small molecules with high informational content (from the perspective of the organism’s need to maintain local and systemic homeostasis), regulated by multispecific SLC and ABC transporters in different body tissues and thereby function similarly to the neuroendocrine system, with which it is functionally intertwined.…”

“…OAT1 (SLC22A6) and OAT3 (SLC22A8) are, like URAT1 (SLC22A12), members of the OAT major clade of the SLC22 transporter family [19*,41]. Indeed, they are among the best known members of this family because, like ABCG2, they are widely regarded as among the major multispecific ‘drug’ transporters of the body [18].…”

“…The question is this: How do combinations of multispecific ‘drug’ transporters (e.g., OAT1, OAT3, ABCG2, MRP2, and MRP4) work together with much more selective uric acid transporters (e.g., URAT1, SLC2A9) – differentially expressed in multiple organs – to maintain plasma, tissue, and nonplasma body fluid levels of uric acid at an optimal level? Here, we attempt to integrate recent findings into a systems physiology view under the framework of the remote sensing and signaling hypothesis regarding inter-organ and inter-organismal (e.g., gut microbiome–host) crosstalk involving organic anions transported by SLC and ABC transporters [11,17,18,19*,20]. Applying the remote sensing and signaling framework to the problem of uric acid homeostasis should help with understanding the systems pathophysiology of hyperuricemia and even suggest new therapeutic approaches.…”