Down-regulation of the organic cation transporter 1 of rat liver in obstructive cholestasis

Denk, Gerald; Soroka, Carol J.; Mennone, Albert; Koepsell, Hermann; Beuers, Ulrich; Boyer, James L.

doi:10.1002/hep.20176

Cited by 61 publications

(44 citation statements)

References 34 publications

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“…22 These discrepancies may be related to strain differences and/or the severity of the cholestatic injury after 7 versus 14 days of CBDL. Ntcp, Oatp1, and Oct1 protein expression decreased in both wild-type and Mrp4Ϫ/Ϫ CBDL mice as previously reported in CBDL rats 21,23,26 and mice, 28,29 although Ntcp reached statistical significance only in the Mrp4Ϫ/Ϫ group (Fig. 4A-B).…”

Section: Cbdl Results In More Liversupporting

confidence: 86%

“…Polyclonal antibodies raised against Mrp2 (Abcc2), Ntcp (Slc10a1), and Oatp1 (Slco1a1) were kindly provided by Bruno Steiger; anti-Mrp4 was a gift from Dietrich Keppler 5 ; Oct1 (Slc22a1) antibodies were provided by Hermann Koepsell. 21 Antibodies to Oatp2 (Slco1a4) and Mdr were purchased from Santa Cruz Biotechnology (Santa Cruz, CA), and Mrp3 (Abcc3) antibodies were developed by our laboratory (Chen et al, unpublished observations). Antibodies to mouse Ost␣ and Ost␤ were kindly provided by Ned Ballatori.…”

Section: Methodsmentioning

confidence: 99%

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Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis

et al. 2006

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Mrp4 is a member of the multidrug resistance-associated gene family that is expressed on the basolateral membrane of hepatocytes and undergoes adaptive upregulation in response to cholestatic injury or bile acid feeding. However, the relative importance of Mrp4 in a protective adaptive response to cholestatic injury is not known. To address this issue, common bile duct ligation (CBDL) was performed in wild-type and Mrp4؊/؊ mice and animals followed for 7 days. Histological analysis and serum aminotransferase levels revealed more severe liver injury in the absence of Mrp4 expression. Western analyses revealed that Mrp4, but not Mrp3, was significantly increased after CBDL in wild-type mice. Serum bile acid levels were significantly lower in Mrp4؊/؊ mice than in wild-type CBDL mice, whereas serum bilirubin levels were the same, suggesting that Mrp4 was required to effectively extrude bile acids from the cholestatic liver. Mrp3 and Ost␣-Ost␤ were upregulated in Mrp4؊/؊ mice but were unable to compensate for the loss of Mrp4. High-performance liquid chromatography analysis on liver extracts revealed that taurine tetrahydroxy bile acid/beta-muricholic acid ratios were increased twofold in Mrp4؊/؊ mice. In conclusion, hepatic Mrp4 plays a unique and essential protective role in the adaptive response to obstructive cholestatic liver injury. ( M ultidrug resistance-associated protein 4 (MRP4) (ABCC4) is an ATP-dependent organic anion transporter with broad substrate specificity. [1][2][3] It is a member of the ABC transporter superfamily 4 and is expressed in a variety of epithelia, including the basolateral and apical plasma membranes of the liver and kidneys, respectively. 5-7 However, this array of substrates and specific tissue localization have not provided insight into Mrp4 function in vivo.Mrp4 was first suggested to play a role in the adaptive response to the hepatic overload of bile acids following the genetic deletion of farnesoid X receptor (FXR), a bile acid sensor. 8,9 A subsequent study suggested that Mrp4 was not elevated upon feeding the hydrophobic bile acid, lithocholic acid. 10 Despite this finding, other studies have demonstrated that hepatic Mrp4 is upregulated in both rats and mice after bile duct ligation 6,11 and in pediatric patients with progressive familial intrahepatic cholestasis. 12 Recent studies demonstrate that MRP4 functions as an efflux pump for bile acids together with glutathione. 13 Further support for a role for MRP4 in hepatic bile acid overload is the recent demonstration that Mrp4 is upregulated by the constitutive androstane receptor. 14 Constitutive androstane receptor is a member of the nuclear hormone receptor superfamily that is required to elevate serum bile acids during cholestatic injury. 15 Cholestatic injury in mice, rats, and humans can also result in adaptive responses in other basolateral transporters. Examples include Mrp3, which is primarily a bilirubin conjugate transporter and also a constitutive androstane receptor target, 15 and the recently described heterodi...

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Section: Cbdl Results In More Liversupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis

et al. 2006

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“…Whereas OCT1 and OCT3 expression has not yet been studied in cholestatic human liver, other hepatocellular uptake transporters such as Na ϩ /taurocholate cotransporter and organic anion transporter OATP1B1 are clearly down-regulated in patients with cholestatic liver disease. 46,47 Interestingly, obstructive and ethinylestradiol-induced cholestasis in rats significantly reduced hepatic Oct1 mRNA and protein levels, [48][49][50] which fits well with our data in humans. Further studies are warranted to elucidate, for instance, whether drug response to the OCT1 and OCT3 substrate metformin is altered in diabetic patients with cholestasis.…”

Section: Discussionsupporting

confidence: 87%

Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver

et al. 2009

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An important function of hepatocytes is the biotransformation and elimination of various drugs, many of which are organic cations and are taken up by organic cation transporters (OCTs) of the solute carrier family 22 (SLC22). Because interindividual variability of OCT expression may affect response to cationic drugs such as metformin, we systematically investigated genetic and nongenetic factors of OCT1/SLC22A1 and OCT3/SLC22A3 expression in human liver. OCT1 and OCT3 expression (messenger RNA [mRNA], protein) was analyzed in liver tissue samples from 150 Caucasian subjects. Hepatic OCTs were localized by way of immunofluorescence microscopy. Matrixassisted laser desorption/ionization time-of-flight mass spectrometry and genome-wide singlenucleotide polymorphism microarray technology served to genotype 92 variants in the SLC22A1-A3/ OCT1-3 gene cluster. Transport of metformin by recombinant human OCT1 and OCT3 was compared using transfected cells. OCT1 mRNA and protein expression varied 113-and 83-fold, respectively; OCT3 mRNA expression varied 27-fold. OCT1 transcript levels were on average 15-fold higher compared with OCT3. We localized the OCT3 protein to the basolateral hepatocyte membrane and identified metformin as an OCT3 substrate. OCT1 and OCT3 expression are independent of age and sex but were significantly reduced in liver donors diagnosed as cholestatic (P < 0.01). Several haplotypes for OCT1 and OCT3 were identified. Multivariate analysis adjusted for multiple testing showed that only the OCT1-Arg61Cys variant (rs12208357) strongly correlated with decreased OCT1 protein expression (P < 0.0001), and four variants in OCT3 (rs2292334, rs2048327, rs1810126, rs3088442) were associated with reduced OCT3 mRNA levels (P ‫؍‬ 0.03). Conclusion: We identified cholestasis and genetic variants as critical determinants for considerable interindividual variability of hepatic OCT1 and OCT3 expression. This indicates consequences for hepatic elimination of and response to OCT substrates such as metformin.

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“…The liver adapts to the higher burden of biliary constituents in part by altering the expression of hepatobiliary transporters. In general, BDL decreases mRNA and protein levels of uptake transporters such as Ntcp, Oatp1a1, Oatp1b2, and Oct1 (Gartung et al, 1996;Dumont et al, 1997;Denk et al, 2004a;Donner et al, 2007). Increased serum and urinary bile acid concentrations observed in rodents after BDL are due, to some extent, to decreased Ntcp and Oatp expression (Lee et al, 2001a;Zollner et al, 2002;Kamisako and Ogawa, 2005).…”

Section: E Bile-duct Ligationmentioning

confidence: 99%

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

2010

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Down-regulation of the organic cation transporter 1 of rat liver in obstructive cholestasis

Cited by 61 publications

References 34 publications

Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis

Mrp4−/− mice have an impaired cytoprotective response in obstructive cholestasis

Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver

Xenobiotic, Bile Acid, and Cholesterol Transporters: Function and Regulation

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