Zonation of Hepatic Bile Salt Transporters

Baier, P.; Hempel, S. L.; Waldvogel, Bettina; Baumgartner, Ulrich

doi:10.1007/s10620-006-3174-3

Cited by 16 publications

(19 citation statements)

References 28 publications

(24 reference statements)

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“…Several sinusoidal membrane transporters (3,8) e.g., sodium-dependent taurocholate cotransporting polypeptide (Ntcp/Slc10a1), and organic anion transporting polyeptides (oatp1a1/Slco1a1, oatp1a4/Slco1a4, oatp1b2/Slco1b2), accept unconjugated bile acids as substrates (9,11,23,26). Their distributions are zonated to the liver as is the case for GAT2: even an acinar distribution for Ntcp and oatp1a1 (3), and pericentral hepatocyte-predominant expression for oatp1a4 (34) and oatp1b2 (8).…”

Section: Discussionmentioning

confidence: 99%

Involvement of γ-aminobutyric acid transporter 2 in the hepatic uptake of taurine in rats

Ikeda

Tachikawa

Akanuma

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Ikeda S, Tachikawa M, Akanuma S-i, Fujinawa J, Hosoya K-i. Involvement of ␥-aminobutyric acid transporter 2 in the hepatic uptake of taurine in rats. Am J Physiol Gastrointest Liver Physiol 303: G291-G297, 2012. First published June 4, 2012; doi:10.1152/ajpgi.00388.2011.-Taurine is essential for the hepatic synthesis of bile salts and, although taurine is synthesized mainly in pericentral hepatocytes, taurine and taurine-conjugated bile acids are abundant in periportal hepatocytes. One possible explanation for this discrepancy is that the active supply of taurine to hepatocytes from the blood stream is a key regulatory factor. The purpose of the present study is to investigate and identify the transporter responsible for taurine uptake by periportal hepatocytes. An in vivo bolus injection of [ 3 H]taurine into the rat portal vein demonstrated that 25% of the injected [3 H]taurine was taken up by the liver on a single pass. The in vivo uptake was significantly inhibited by GABA, taurine, ␤-alanine, and nipecotic acid, a GABA transporter (GAT) inhibitor, each at a concentration of 10 mM. The characteristics of Na ϩ -and Cl Ϫ -dependent [3 H]taurine uptake by freshly isolated rat hepatocytes were consistent with those of GAT2 (solute carrier SLC6A13). Indeed, the Km value of the saturable uptake (594 M) was close to that of mouse SLC6A13-mediated taurine transport. Although GABA, taurine, and ␤-alanine inhibited the [ 3 H]taurine uptake by Ͼ 50%, each at a concentration of 10 mM, GABA caused a marked inhibition with an IC50 value of 95 M. The [ 3 H]taurine uptake exhibited a significant reduction when the GAT2 gene was silenced. Immunohistochemical analysis showed that GAT2 was localized on the sinusoidal membrane of the hepatocytes predominantly in the periportal region. These results suggest that GAT2 is responsible for taurine transport from the circulating blood to hepatocytes predominantly in the periportal region. taurine conjugation; hepatocyte; periportal; heterogenity; carrier-mediated transport TAURINE IS ESSENTIAL FOR THE hepatic synthesis of bile salts, such as taurocholate and taurochenodeoxycholate, which are required for the intestinal absorption of fats and lipid-soluble vitamins (5). To date, hepatocyte heterogeneity has been proposed with regard to the biosynthesis of bile salts: taurine conjugation with bile acids and taurine biosynthesis from cysteine preferentially occurs in the periportal lobular periphery (39) and pericentral hepatocytes (32), respectively. Indeed, bile acid-CoA-amino acid N-acyltransferase (BAAT) mRNA, the enzyme involved in the conjugation of taurine and glycine with cholic acid, has been found in higher concentrations in periportal hepatocytes (13). In contrast, [32 S]cysteine is incorporated into taurine much faster in pericentral hepatocytes (32). This discrepancy between the sites of taurine synthesis and its conjugation could be explained by the supply of taurine from the circulating blood to periportal hepatocytes. In support of this hypothesis, oral administration of...

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Section: Discussionmentioning

confidence: 99%

Involvement of γ-aminobutyric acid transporter 2 in the hepatic uptake of taurine in rats

Ikeda

Tachikawa

Akanuma

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Molecular identification and func- tional studies showed the transport of the unconjugated form of bile acid by bile acid transporters expressed at the sinusoidal membrane. [73][74][75][76] The reconjugation of taurine and de novo synthesis of taurine-conjugated bile salts have recently been suggested to occur through the coupling of oatp1a1 (Slco1a1), Ntcp (Slc10a1) and GAT2 in periportal hepatocytes, because of their acinar distribution and pericentral-dominant expression of oatp1b2 (Slco1b2) and oatp1a4 (Slco1a4). [74][75][76] 6.…”

Section: Hepatic Taurine Uptake Mediated By Gat2mentioning

confidence: 99%

“…[73][74][75][76] The reconjugation of taurine and de novo synthesis of taurine-conjugated bile salts have recently been suggested to occur through the coupling of oatp1a1 (Slco1a1), Ntcp (Slc10a1) and GAT2 in periportal hepatocytes, because of their acinar distribution and pericentral-dominant expression of oatp1b2 (Slco1b2) and oatp1a4 (Slco1a4). [74][75][76] 6. STRUCTURAL BASIS OF TAURINE AND GABA TRANSPORT BY TAUT Among Na + -and Cl − -dependent transporters belonging to SLC6A family, TauT is reported to have a lower affinity (1.5 mM) for GABA than GATs (<80 µM), 10,11) while the amino acid sequence of GATs is similar to that of TauT, 77,78) and the molecular basis of this different affinity has been an important topic in understanding the substrate specificity of SLC6A family members.…”

Section: Hepatic Taurine Uptake Mediated By Gat2mentioning

confidence: 99%

Impact of SLC6A Transporters in Physiological Taurine Transport at the Blood–Retinal Barrier and in the Liver

Kubo

Akanuma

Hosoya

2016

Biological & Pharmaceutical Bulletin

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Cumulative studies showed that taurine (2-aminoethanesulfonic acid) contributes to a variety of physiological events. Transport study suggested the cellular taurine transport in an Na -and Cl -dependent manner, and the several members of SLC6A family have been shown as taurine transporter. At the inner blood-retinal barrier (BRB), taurine transporter (TauT/SLC6A) is involved in the transport of taurine to the retina from the circulating blood. The involvement of TauT is also suggested in γ-aminobutyric acid (GABA) transport at the inner BRB, and its role is assumed in the elimination of GABA from the retinal interstitial fluid. In the retina, taurine is thought to be a major organic osmolyte, and its influx and efflux through TauT and volume-sensitive organic osmolyte and anion channel (VSOAC) in Müller cells regulate the osmolarity in the retinal microenvironment to maintain a healthy retina. In the liver, hepatocytes take up taurine via GABA transporter 2 (GAT2/SLC6A13, the orthologue of mouse GAT3) expressed at the sinusoidal membrane of periportal hepatocytes, contributing to the metabolism of bile acid. Site-directed mutagenesis study suggests amino acid residues that are crucial in the recognition of substrates by GATs and TauT. The evidence suggests the physiological impact of taurine transporters in tissues.

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“…84 In the gradient type, all hepatocytes are able to express a particular gene, but the level of expression depends on the position of the hepatocyte along the portocentral radius. Examples include key regulatory enzymes of carbohydrate metabolism, cytosolic phosphoenol-pyruvate carboxykinase I (PCK) and glucokinase.…”

Section: Regulation Of the Hepatic Microcirculationmentioning

confidence: 99%

“…In the case of bile formation, physiological availability of biliary solutes in periportal blood is a major determinant, independent of hepatocellular expression of relevant transporters. 84 Likewise, gradients of oxygen and hormones across the lobule are thought to play key roles influencing expression of metabolic enzymes. 80 Recently, it has been shown that the Wnt/β-catenin signalling pathway plays a key role in regulating liver zonation.…”

Section: Plasma Membranementioning

confidence: 99%