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LIVER AND BILIARY TRACT
-OST
in cholestasis in humans and rodents
1Liver Center, Yale University School of Medicine, New Haven, Connecticut; 2Division of Gastroenterology and Hepatology, Department of Medicine, Medical University, Graz, Austria; and the 3Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York
Submitted 28 November 2005 ; accepted in final form 11 January 2006
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ABSTRACT |
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-OST
) is a novel heteromeric bile acid and sterol transporter expressed at the basolateral membranes of epithelium in the ileum, kidney, and liver. To determine whether OST-OST undergoes farnesoid X receptor (FXR)-dependent adaptive regulation following cholestatic liver injury, mRNA and protein expression levels were analyzed in patients with primary biliary cirrhosis (PBC) and following common bile duct ligation (CBDL) in rats and Fxr null and wild-type mice. Hepatic OST and OST mRNA increased 3- and 32-fold, respectively, in patients with PBC compared with controls, whereas expression of Ost and Ost also increased in the liver of rats and mice following CBDL. In contrast, expression of Ost and Ost mRNA was generally lower in Fxr null mice, and CBDL failed to enhance expression of Ost and Ost compared with wild-type mice. HepG2 cells treated for 24 h with chenodeoxycholic acid, a selective FXR ligand, had higher levels of OST and OST mRNA and protein. Increases in OST protein were visualized by confocal microscopy at the plasma membrane. These results indicate that expression of Ost and Ost are highly regulated in response to cholestasis and that this response is dependent on the FXR bile acid receptor.
bile acid and steroid transporter; primary biliary cirrhosis; cholangiocytes; kidney; bile acid reabsorption
-OST) is a heteromeric transporter expressed on the basolateral membrane of epithelial cells of human ileum, liver, and kidney that functions to extrude bile acids and other organic solutes and steroids from these and other tissues (2, 3, 7, 22, 29). OST-OST is known to transport estrone 3-sulfate, dehydroepiandrosterone 3-sulfate, taurocholate, digoxin, and prostaglandin E2 (22, 29), as well as a variety of other bile acids (3). This transporter was originally cloned from the liver of an evolutionarily ancient vertebrate, the small skate Leucoraja erinacea (29), and was subsequently discovered to have orthologs in mammals, including humans (22). Recent studies (7) indicate that murine Ost-Ost is a basolateral transporter that is highly expressed in the epithelial cells of the terminal ileum of the mouse and is responsible for the export of bile acids to mesenteric blood following their uptake by the apical sodium-dependent bile acid transporter Asbt (Slc10A2). Subsequent studies have demonstrated that both OST and OST are also expressed in the kidney and in cholangiocytes in rodents and human, where bile acids are also taken up by ASBT (3). Although expression in the kidney and liver varies between species, localization of Ost-Ost at the basolateral membrane of the mouse and rat proximal renal tubule and cholangiocyte also supports its role as a major bile acid efflux transporter in these cells (3).
It is now well established, based on studies in rodents as well as human cholestatic liver disease, that other bile acid transporters, including NTCP (SLC10A1), bile salt export pump (BSEP; ABCB11), and ASBT (SLC10A2), all undergo adaptive responses both to cholestatic liver injury and to bile acid feeding and that these responses can be interpreted as protecting the tissue from the toxic effects of bile acid accumulation (5, 26, 27). Furthermore, studies in common bile duct-ligated (CBDL) mice indicate that these changes in bile acid transporter expression are regulated by the bile acid-activated nuclear receptor farnesoid X receptor (FXR, NR1H4) (28, 32). Therefore, we hypothesized that the subunits of OST might also undergo adaptive regulation in response to cholestatic liver injury and be regulated by FXR. To examine this question, the expression of OST-OST was examined in patients with cholestatic liver injury and after CBDL in mice and rats. In addition, to determine whether these adaptive responses depended on Fxr, CBDL was also carried out in Fxr–/– mice, and human hepatoma cells were treated with chenodeoxycholic acid (CDCA), a potent FXR ligand. Our findings indicate that cholestasis results in a significant adaptive response in OST-OST in the liver of humans and rodents, although the levels of expression vary between subunits and species. Furthermore, the results indicate that these responses are critically dependent on the nuclear receptor FXR. These findings are consistent with the hypothesis that OST-OST is a basolateral bile salt transporter that is likely to have a significant role in protecting the liver from the accumulation of bile salts during cholestatic liver injury.
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METHODS |
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All experimental protocols were approved by the local Animal Care and Use Committee, according to criteria outlined in the "Guidelines for the Care and Use of Laboratory Animals" prepared by the National Academy of Sciences, as published by the NIH (publication 86–23, revised 1985).
Tissue specimens and patients characteristics. Fifteen liver specimens comprising samples from patients with primary biliary cirrhosis (PBC; n = 11), and controls without liver disease (n = 4) were analyzed. PBC specimens were obtained during liver transplantation. The diagnosis of PBC was based on standard criteria (13, 14). Six patients had PBC stage III (PBC III), and five had stage IV (PBC IV) according to Ludwig (19). Most PBC patients (4 of 6 PBC III; 3 of 5 PBC IV) received standard ursodeoxycholic acid (UDCA) treatment. Normal liver tissue was obtained from patients undergoing resection of liver metastases. All of the specimens were analyzed previously (31). Liver tissue was immediately snap frozen and stored in liquid nitrogen until analysis. All patients had given their informed consent for the study, and the experimental protocol was approved by the local ethics committees in accordance with the ethical guidelines of the 1975 Declaration of Helsinki.
HepG2 cell experiments.
The human hepatocellular carcinoma cell line HepG2 was acquired from ATCC (Manassas, VA) and used without testing for mycoplasmal contamination. Cells were cultured in DMEM containing 10% FBS and 1% penicillin-streptomycin at 37°C with 5% CO2. When cells reached 
70% confluence, they were washed and cultured in fresh, serum-depleted medium in the presence or absence of 50 µM CDCA (Sigma, St. Louis, MO). Twenty-four hours after CDCA addition, cells were collected by directly applying TRIzol (Invitrogen, Carlsbad, CA) to the culture dish for total RNA isolation and quantitative PCR was preformed as described below.
For immunoblot analyses, HepG2 cells were washed with PBS before being scraped in 1 ml of ice-cold homogenizing buffer containing 10 mM Tris·HCl (pH 7.4), 10 mM KCl, 1.5 mM MgCl2, 10 µl/ml protease inhibitor cocktail (Sigma), 2 mM PMSF, and 0.68 mM EDTA. Cells were homogenized with 35 strokes using type A pestle of a Dounce homogenizer while in ice. Sucrose was added to a final concentration of 250 mM, and the homogenate was centrifuged at 800 g for 20 min at 4°C. The supernatant was collected and stored at –80°C, and protein concentration was determined by the Lowry assay (18). Cell homogenates were dissolved in Pierce lane marker sample buffer (Pierce, Rockford, IL) supplemented with -mercaptoethanol, incubated at 37°C for 30 min, brought to room temperature, and subjected to SDS-PAGE.
For immunofluorescence analysis, HepG2 cells were fixed with cold methanol 24 h after addition of 50 µM CDCA or 100 µM UDCA. Cells were incubated 20 min in blocking buffer (PBS, 1% BSA, 0.05% Triton X-100) followed by 2 h in antibody to OST and OST diluted 1:150 in blocking buffer. After being washed 30–45 min in PBS-0.05% Triton X-100, Alexa 594 anti-rabbit IgG (Invitrogen) was incubated for 1 h at room temperature. Fluorescence was visualized with a Zeiss LSM510 (Carl Zeiss, Thornwood, NY) confocal microscope, and images were processed with Photoshop (Adobe, Mountainview, CA).
Real-time RT-PCR. Total RNA was isolated from liver using TRIzol reagent according to manufacturer's protocol (Invitrogen). Total RNA (5 µg) was reverse transcribed using Pro-Star first-strand kit (Stratagene, La Jolla, CA) with oligo(dT) according to the supplier's protocol. Quantitative PCR was performed using Applied Biosystems 7500 DNA sequence detector system in a total volume of 20 µl with either Platinum SYBR green master mix, Platinum quantitative PCR supermix-UDG (Invitrogen), or TaqMan universal master mix (Applied Biosystems, Foster City, CA). Specific primer pairs and probes were designed (Table 1) or purchased (TaqMan gene expression assays, Applied Biosytems) and used for quantitative PCR analysis. The detection procedure was as follows: 50°C for 2 min, 95°C 10 min, then 40 cycles at 95°C for 15 s, followed by 60°C for 1 min. At the end of the PCR, a dissociation curve was set from 60 to 95°C to ensure the quantification/amplification of single PCR products if SYBR green was the detector. Relative target quantity was determined from the standard curve and normalized to either 18S ribosomal RNA or GAPDH expression.
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Western blot analysis.
Similar amounts of protein (20–100 µg) were subjected to SDS-PAGE. Equal protein loading was confirmed by Coomassie blue staining of gels and Ponceau S staining of membranes. After electrotransfer to nitrocellulose membranes (Bio-Rad, Hercules, CA), blots were blocked with 5% nonfat milk in Tris-buffered saline containing 0.1% Tween 20 for 1 h at room temperature and incubated overnight at 4°C with primary antibodies. OST and OST polyclonal antibodies were generated as previously described (3). Monoclonal anti--actin antibodies and horseradish peroxidase-conjugated secondary antibodies were from Sigma, and enhanced chemiluminescence reagents were from Amersham Pharmacia Biotech (Piscataway, NJ). Densitometry was performed with Multi-Analyst software (Bio-Rad).
Statistics. Data are expressed as the means ± SD. Differences between specific groups were determined using an unpaired Student's t-test and analyzed by the Instat software package (GraphPad Software, San Diego, CA). Data without error bars represent pooled samples.
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RESULTS |
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and OST/Ost mRNA and protein are induced in human and rodent cholestatic liver
Human liver.
mRNA and protein samples from human cholestatic livers were obtained from a series of patients with primary biliary cirrhosis (31). Both OST and OST are more highly expressed in normal human liver than rodent livers (3), and the hepatic expression of these subunits in humans is more comparable with the marine skate from which the original genes were cloned (29). Figure 1, A and B, demonstrates that there are significant increases in the mRNA and protein of both these subunits in patients with primary biliary cirrhosis with a threefold increase in OST mRNA and a marked 32-fold increase in OST mRNA compared with control human liver. OST protein expression also increased approximately two- to threefold for the -subunit and four- to fivefold for the -subunit (Fig. 1B).
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mRNA in liver was reduced at days 3 and 7 but unchanged compared with sham controls at day 14 (Fig. 2A). In contrast to Ost mRNA, Ost protein was significantly upregulated fourfold at day 14 (Fig. 2B). Remarkably, Ost mRNA was upregulated 100-fold at day 7 and 70-fold at day 14 (Fig. 2A). Although Ost protein was not detectable by Western blotting of a whole rat liver total membrane fraction, it could be weakly detected by immunofluorescence in cholangiocytes and hepatocytes (data not shown). Quantitative PCR analysis of mRNA obtained from isolated rat hepatocytes and from rat bile duct tissue demonstrated that the upregulation of Ost occurs predominantly in hepatocytes rather than in cholangiocytes (Fig. 2C).
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and Ost mRNA response to day 3, 7, and 14 bile duct ligation in the mouse. There were no significant changes in Ost mRNA, whereas Ost mRNA increased by 20-fold at day 3, 21-fold at day 7, and 2.5-fold after day 14 following common bile duct obstruction. However, a progressive increase in Ost protein was seen over the 14-day time course. As was the case in rat liver, Ost protein was undetectable in total membrane fractions of whole mouse liver, although it was weakly visible by immunofluorescence in the basolateral membrane in cholangiocytes (data not shown).
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in CBDL mice.
To determine whether the changes in expression of these two subunits are dependent on the action of the nuclear receptor Fxr, studies were carried out before and after bile duct ligation in control and Fxr–/– mice. Bile duct ligation in Fxr–/– mice failed to enhance expression of Ost and Ost compared with wild-type mice (Fig. 4). As seen in Fig. 4A, there were no significant changes in hepatic Ost mRNA levels after 3 days of CBDL in either the Fxr+/+ or Fxr–/– mouse. However, there was a small but significant twofold increase at day 7 in wild-type CBDL mice but not Fxr–/– day-7 CBDL mice. Furthermore, the highly significant changes in Ost mRNA expression in wild-type mice were completely abrogated 3 and 7 days following CBDL in the Fxr–/– mouse, indicating complete dependence of the induced expression of the -subunit on the presence of Fxr (Fig. 4B).
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and OST expression in HepG2 cells.
To further test the hypothesis that FXR is involved in the cholestasis-induced changes in OST and OST expression, transcript abundance of OST and OST was measured in HepG2 cells treated with the FXR ligand CDCA. OST and OST mRNA were markedly increased in cells treated for 24 h with CDCA (Fig. 5A). The effect on OST mRNA (70-fold increase) was larger than on OST (18-fold increase), consistent with the in vivo studies in human and rodent liver described previously. BSEP and SHP mRNA levels were also found to be increased after CDCA treatment (Fig. 5A), consistent with previous reports that they are FXR regulated (12, 23). These changes in mRNA were accompanied by large increases in OST protein and smaller changes in OST protein (Fig. 5B). Note that the OST protein appears on Western blots as two bands of 36 and 40 kDa. These probably represent the unmodified and glycosylated forms of the polypeptide, respectively (7). Immunofluorescent studies of HepG2 cells treated with 50 µM CDCA revealed a large increase in staining of the plasma membrane for OST and OST (Fig. 6, B and E) that was not evident in untreated cells (Fig. 6, A and D) or cells treated with 100 µM UDCA (Fig. 6, C and F), suggesting both an upregulation and a possible redistribution of the protein to the plasma membrane.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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and OST in cholestasis in humans and rodents and provide evidence that these adaptive responses are regulated by the nuclear receptor FXR. OST and OST are two recently described proteins whose simultaneous expression at the basolateral membrane of cells results in a novel organic solute carrier (2, 3, 7, 22, 29). In the ileum, where these solute carriers are most highly expressed, OST and OST presumably function physiologically as critical components of the enterohepatic circulation of bile acids by transporting them from the enterocytes to the splanchnic circulation for subsequent first pass extraction by bile salt transporters in the liver. This conclusion is based on the ability of the bile salt taurocholate to move from luminal to the basolateral compartments of MDCK cells in transwells only when both subunits are expressed (7) and by efflux of taurocholate in Xenopus oocytes expressing OST and OST (3). Bile acids can also be transported into cholangiocytes and the renal proximal tubule by ASBT (6, 17). Cholangiocyte ASBT presumably contributes to the cholehepatic shunting of bile salts, which is more prominent in cholestatic liver injury where bile ducts are proliferated, whereas the renal ASBT normally recycles bile acids from the lumen of the proximal tubule after they are filtered at the glomerulus (17). Localization of Ost and Ost to the basolateral membranes of cholangiocytes and proximal tubule of the kidney (3) strongly suggests that these proteins form the functional transporter that completes the cholehepatic and renal-systemic shunting of bile acids and possibly other organic solutes and steroids.
The present study extends these prior observations by examining the effects of cholestasis on the expression of these two subunits in cholestatic liver disease in human and in rodent models of obstructive cholestasis. Although the findings reveal species differences in the magnitude of this response, they support the above-predicted physiological role. The expression of OST-OST in the human liver is higher than in rodent liver, as previously reported (7, 22). Thus, in the present study, the most significant results come from the changes of expression of this transporter in human livers from patients with primary biliary cirrhosis. Both - and -subunits are upregulated in these patients both at the mRNA level and in Western blot analysis of tissue protein. In the rat and mouse, Ost protein is also significantly increased in the liver after CBDL. Competition transport studies indicate that sulfated and/or amidated bile acids are more powerful inhibitors of transport than the corresponding parent compounds (22, 29), suggesting that these are better substrates for Ost-Ost. Thus the present findings in cholestatic liver are consistent with the known substrate specificity of Ost. Furthermore, in HepG2 cells, exposure to CDCA induced a dramatic increase in the amount of the OSTs located at the plasma membrane, suggesting that increases in tissue levels of bile acids are providing the stimulus for a possible translocation to the plasma membrane. Thus bile acids may have both transcriptional as well as posttranscriptional effects on OST expression.
Differences were observed after cholestasis between the level of expression of OST/Ost and OST/Ost both within and between species, which are not currently explained. However, it should be noted that neither the mechanism by which OST/Ost and OST/Ost interact, their individual roles in generating a functional complex at the plasma membrane, nor their individual roles in solute transport have yet been identified. Although both proteins are required to elicit transport activity, there is as yet no evidence that they combine in any particular stoichiometry. Indeed, studies of Dawson et al. (7) indicate that Ost may function as a chaperone or catalyst for delivery of mouse Ost to the plasma membrane because coexpression of Ost and Ost was required to convert the Ost subunit to a mature N-glycosylated endo H-resistant form. This suggests that coexpression facilitates the movement of Ost through the Golgi apparatus.
Previous studies (26, 28) clearly demonstrate that all other major transporters for bile acids in the enterohepatic circulation undergo adaptive regulation in the cholestatic liver in a manner that would help protect these tissues from bile acid accumulation and tissue injury. Furthermore, several of these changes in transporter expression are either directly or indirectly regulated by Fxr, the bile acid nuclear receptor (5, 28). Thus NTCP and Asbt are indirectly downregulated by the action of the short heterodimeric protein SHP-1 on their promoters (8), and expression of SHP-1 is positively upregulated by bile acid activation of FXR (12). In contrast, BSEP and the ileal bile salt binding protein (I-BABP) contain FXR response elements in their promoters, so their expression is directly and positively upregulated by bile acid activation of FXR (23). Thus it is logical to expect that if OST-OST is an important component of the enterohepatic, cholehepatic, and renal-systemic circulations of bile acids, its expression should also be regulated by FXR. To assess this directly, we used the Fxr–/– mouse model in which it has been demonstrated that adaptive responses of Bsep, Shp-1, Ntcp, and the I-babp after bile duct ligation or cholic acid feeding depend on the presence of Fxr (28). The results of the present study clearly confirm this expectation by demonstrating that the induction of mouse liver Ost mRNA by CBDL is completely abolished in the Fxr–/– mouse. Regulation of both mouse and human OST/Ost and OST/Ost by FXR has also been recently confirmed (10, 15, 16, 33). Thus it is likely that OST-OST is the key transporter whose induction at the basolateral membrane of hepatocytes, cholangiocytes, and proximal tubule epithelia contributes to the adaptive response seen in cholestasis.
Several MRP/Mrps are also located at the basolateral membrane of hepatocytes and cholangiocytes, and their expression is upregulated in human cholestatic liver disease and obstructive cholestasis in rats and mice (9, 24, 31). Furthermore, MRP3/Mrp3 and MRP4/Mrp4 both are capable of transporting divalent bile acid conjugates in in vitro expression systems (1, 26). Although the functional significance of changing levels of expression of different transporters is difficult to compare, the quantitative increases seen in the present studies for the Osts after bile duct ligation in the mouse are much higher than previously observed for mouse Mrp3 and Mrp4 (28). Previous studies have shown that the induction of OST-OST is also more profound than the induction of MRP3 and MRP4 in human cholestatic liver. Notably, the OSTs undergo extensive regulation at the mRNA level, which was not seen for human MRP3 and MRP4 (31). Although studies of the effects of bile duct ligation on Mrp3 and Mrp4 expression in their respective knockout mouse models suggest that both contribute to liver tissue protection [with Mrp4 having the greater role as a bile acid conjugate efflux pump (4, 20, 30)], Ost-Ost may well provide the predominant response. Future studies in Ost-Ost knockout mice may address these issues. The present studies provide the first evidence for a basolateral transporter to be directly regulated by FXR in cholestasis. Mrp3 and Mrp4 are Fxr independent and are even induced to a higher extent in cholestatic and bile acid-challenged Fxr knockout mice (28). Thus the OSTs may be the long-sought missing link in the adaptive response to toxic bile acids.
It remains unclear why there are such profound differences in expression of OST/Ost and OST/Ost between species. Although the original transcripts were cloned from a marine skate liver library as part of an effort to identify novel organic solute transporters, message levels were found for these transcripts in a wide variety of skate tissues (22, 29). In humans, the highest expression of OST is liver > testes > intestinal tissue > kidney, whereas the -subunit is expressed most highly in testes > intestine > kidney > adrenal gland > liver, although it should be noted that ileum was not specifically selected in those studies (22). Nevertheless, the widespread expression of these proteins in human tissues and their ability to transport a wide range of organic solutes, including the steroids taurocholate, estrone 3-sulfate, dehydroepiandrosterone sulfate, and digoxin as well as the eicosanoid prostaglandin E2, suggests that bile acid transport is not their only function (3, 22, 29). Although future studies should examine these questions, the present findings strongly support a major role for OST/Ost and OST/Ost as part of the adaptive response of bile acid transport proteins to limit the recycling and tissue accumulation of bile acids during cholestasis, particularly in human liver where these subunits are more highly expressed.
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GRANTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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REFERENCES |
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-OST. Exp Biol Med 230: 689–698, 2005.-OST: a major basolateral bile acid and steroid transporter in human intestinal, renal, and biliary epithelia. Hepatology 42: 1270–1279, 2005.[CrossRef][Web of Science][Medline]-, Ost-Ost, is an ileal basolateral bile acid transporter. J Biol Chem 280: 6960–6968, 2005.-, Ost-Ost, by bile acids. Am J Physiol Gastrointest Liver Physiol 290: G912–G922, 2006. and - genes. Am J Physiol Gastrointest Liver Physiol 290: G476–G485, 2006. and in the adrenal gland, kidney and intestine. J Lipid Res 47: 201–214, 2006.-OST. J Biol Chem 278: 27473–27482, 2003./ in the adaptive response to bile acids. Am J Physiol Gastrointest Liver Physiol 290: G923–G932, 2006.This article has been cited by other articles:
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  P. A. Dawson, T. Lan, and A. Rao Bile acid transporters J. Lipid Res., December 1, 2009; 50(12): 2340 - 2357. [Abstract] [Full Text] [PDF]
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J. Y. L. Chiang Bile acids: regulation of synthesis J. Lipid Res., October 1, 2009; 50(10): 1955 - 1966. [Abstract] [Full Text] [PDF]
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 I. L. Csanaky, L. M. Aleksunes, Y. Tanaka, and C. D. Klaassen Role of hepatic transporters in prevention of bile acid toxicity after partial hepatectomy in mice Am J Physiol Gastrointest Liver Physiol, September 1, 2009; 297(3): G419 - G433. [Abstract] [Full Text] [PDF]
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 M. Ogura, S. Nishida, M. Ishizawa, K. Sakurai, M. Shimizu, S. Matsuo, S. Amano, S. Uno, and M. Makishima Vitamin D3 Modulates the Expression of Bile Acid Regulatory Genes and Represses Inflammation in Bile Duct-Ligated Mice J. Pharmacol. Exp. Ther., February 1, 2009; 328(2): 564 - 570. [Abstract] [Full Text] [PDF]
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 J. J. Eloranta and G. A. Kullak-Ublick The Role of FXR in Disorders of Bile Acid Homeostasis Physiology, October 1, 2008; 23(5): 286 - 295. [Abstract] [Full Text] [PDF]
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O. Renner, S. Harsch, A. Strohmeyer, S. Schimmel, and E. F. Stange Reduced ileal expression of OST{alpha}-OST{beta} in non-obese gallstone disease J. Lipid Res., September 1, 2008; 49(9): 2045 - 2054. [Abstract] [Full Text] [PDF]
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N. Ballatori, F. Fang, W. V. Christian, N. Li, and C. L. Hammond Ost{alpha}-Ost{beta} is required for bile acid and conjugated steroid disposition in the intestine, kidney, and liver Am J Physiol Gastrointest Liver Physiol, July 1, 2008; 295(1): G179 - G186. [Abstract] [Full Text] [PDF]
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M. G. Donner, S. Schumacher, U. Warskulat, J. Heinemann, and D. Haussinger Obstructive cholestasis induces TNF-{alpha}- and IL-1 -mediated periportal downregulation of Bsep and zonal regulation of Ntcp, Oatp1a4, and Oatp1b2 Am J Physiol Gastrointest Liver Physiol, December 1, 2007; 293(6): G1134 - G1146. [Abstract] [Full Text] [PDF]
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 S.-Y. Cai, L. Xiong, C. G. Wray, N. Ballatori, and J. L. Boyer The farnesoid X receptor FXR{alpha}/NR1H4 acquired ligand specificity for bile salts late in vertebrate evolution Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1400 - R1409. [Abstract] [Full Text] [PDF]
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A.-Q. Sun, N. Balasubramaniyan, K. Xu, C. J. Liu, V. M. Ponamgi, H. Liu, and F. J. Suchy Protein-protein interactions and membrane localization of the human organic solute transporter Am J Physiol Gastrointest Liver Physiol, June 1, 2007; 292(6): G1586 - G1593. [Abstract] [Full Text] [PDF]
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S. J. Keely, M. M. Scharl, L. S. Bertelsen, L. R. Hagey, K. E. Barrett, and A. F. Hofmann Bile acid-induced secretion in polarized monolayers of T84 colonic epithelial cells: structure-activity relationships Am J Physiol Gastrointest Liver Physiol, January 1, 2007; 292(1): G290 - G297. [Abstract] [Full Text] [PDF]
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