Novel liver-specific organic anion transporter OAT7 that operates the exchange of sulfate conjugates for short chain fatty acid butyrate.
The liver plays an important role in the elimination of endogenous and exogenous lipophilic organic compounds from the body, which is mediated by various carrier proteins that differ in substrate specificity and kinetic properties. Here, we have characterized a novel member of the organic anion transporter family (SLC22) isolated from human liver. The transporter named organic anion transporter 7 (OAT7/ SLC22A9) showed 35% to 46% identities to those of other organic anion transporters of SLC22 family. When expressed in Xenopus oocytes, OAT7 mediated Na(+)-independent, high-affinity transport of sulfate-conjugated steroids, estrone sulfate (ES; K(m) = 8.7 microM), and dehydroepiandrosterone sulfate (K(m) = 2.2 microM). In addition, OAT7 interacted with negatively charged sulfobromophthalein, indocyanine green, and several sulfate-conjugated xenobiotics. In contrast, glucuronide and glutathione conjugates exhibited no inhibitory effects on OAT7-mediated [(3)H]ES transport. OAT7-mediated [(3)H]ES transport was trans-stimulated by three-carbon to five-carbon (C3 to C5) short-chain fatty acids. The efflux of [(14)C]butyrate (C4) via OAT7 was significantly trans-stimulated by extracellular ES. Furthermore, OAT7 mediated [(14)C]butyrate uptake and [(3)H]ES efflux in exchange for extracellular butyrate both in Xenopus oocytes and OAT7-stably expressing cells. OAT7 protein was localized in the sinusoidal membrane of hepatocytes by immunohistochemical analysis.


CONCLUSIONS
OAT7 is the first liver-specific transporter among members of the organic anion transporters of SLC22 family. Our findings suggest a new class of substrates for organic anion transporters and provide evidence for the transport of anionic substances such as sulfate-conjugates in exchange for butyrate in hepatocytes.
Shin
Ho Jung
HJ
Department of Pharmacology and Toxicology, Kyorin University, School of Medicine, Tokyo, Japan.
Anzai
Naohiko
N
Enomoto
Atsushi
A
He
Xin
X
Kim
Do Kyung
DK
Endou
Hitoshi
H
Kanai
Yoshikatsu
Y
D000838:Anions / Q000378:metabolism; D002087:Butyrates / Q000378:metabolism*; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D005232:Fatty Acids, Volatile / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000201:enzymology*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D013256:Steroids / Q000378:metabolism; D013379:Substrate Specificity; D013431:Sulfates / Q000378:metabolism*; D015262:Xenobiotics / Q000378:metabolism
D000838:Anions; D002087:Butyrates; D005232:Fatty Acids, Volatile; D029362:Organic Anion Transporters, Sodium-Independent; C427207:SLC22A11 protein, human; D013256:Steroids; D013431:Sulfates; D015262:Xenobiotics; D004970:Estrone; C017296:estrone sulfate