Changes in the expression and localization of hepatocellular transporters and radixin in primary biliary cirrhosis

Kojima, Hideyuki; Nies, Anne T.; König, Jörg; Hagmann, Wolfgang; Spring, Herbert; Uemura, Mamoru; Fukui, Hiroshi; Keppler, Dietrich

doi:10.1016/s0168-8278(03)00410-0

Cited by 147 publications

(111 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

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

Self Cite

View full text Add to dashboard Cite

show abstract

“…Under these conditions, immunostaining of Abcc2 is no longer confined to the canalicular membrane, but appears "fuzzy," which is interpreted as an accumulation of transporter molecules within the hepatocyte. A comparable fuzzy immunostaining, indicative of endocytic retrieval of transporter molecules, has been described in human liver diseases, e.g., inflammation-induced icteric cholestasis [189], obstructive cholestasis [153,186], and advanced stages of primary biliary cirrhosis [88,101].…”

Section: Transcriptional and Posttranscriptional Regulation Of Abcc2supporting

confidence: 63%

“…Radixin, a member of the ezrin/radixin/moesin family cross-linking actin with several integral membrane proteins [10], is apparently required for the proper apical localization of Abcc2 because radixin knock-out mice exhibit conjugated hyperbilirubinemia and a selective loss of the Abcc2 protein from the hepatocyte canalicular membrane [84]. Canalicular localization of human ABCC2 may similarly be dependent on radixin interaction [88]. Other proteins interacting with ABCC2 in vitro belong to the PSD95/Dlg/ZO-1 (PDZ) family and bind to C termini with the conserved sequence T/S-X-Φ, with X being any amino acid and Φ a hydrophobic amino acid.…”

Section: Localization Of Abcc2 In Polarized Cells and Tissuesmentioning

confidence: 99%

The apical conjugate efflux pump ABCC2 (MRP2)

Nies

Keppler

2006

Pflugers Arch - Eur J Physiol

Self Cite

349

247

View full text Add to dashboard Cite

ABCC2 is a member of the multidrug resistance protein subfamily localized exclusively to the apical membrane domain of polarized cells, such as hepatocytes, renal proximal tubule epithelia, and intestinal epithelia. This localization supports the function of ABCC2 in the terminal excretion and detoxification of endogenous and xenobiotic organic anions, particularly in the unidirectional efflux of substances conjugated with glutathione, glucuronate, or sulfate, as exemplified by leukotriene C 4 , bilirubin glucuronosides, and some steroid sulfates. The hepatic ABCC2 pump contributes to the driving forces of bile flow. Acquired or hereditary deficiency of ABCC2, the latter known as Dubin-Johnson syndrome in humans, causes an increased concentration of bilirubin glucuronosides in blood because of their efflux from hepatocytes via the basolateral ABCC3, which compensates for the deficiency in ABCC2-mediated apical efflux. In this article we provide an overview on the molecular characteristics of ABCC2 and its expression in various tissues and species. We discuss the transcriptional and posttranscriptional regulation of ABCC2 and review approaches to the functional analysis providing information on its substrate specificity. A comprehensive list of sequence variants in the human ABCC2 gene summarizes predicted and proven functional consequences, including variants leading to Dubin-Johnson syndrome. Keywords

show abstract

“…This approach-taking mildly diseased livers as controls-was already used in other studies of human cholestatic conditions. [41][42][43] Despite the limitations and small sample sizes, some clear differences were detectable between PFIC livers and controls.…”

Section: Discussionmentioning

confidence: 99%

Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis

et al. 2005

Self Cite

View full text Add to dashboard Cite

Mutations of the bile salt export pump (BSEP) or the multidrug resistance P-glycoprotein 3 (MDR3) are linked to impaired bile salt homeostasis and lead to progressive familial intrahepatic cholestasis (PFIC)-2 and -3, respectively. The regulation of bile salt transporters in PFIC is not known. Expression of hepatobiliary transporters in livers of ten patients with a PFIC phenotype was studied by quantitative reverse transcription polymerase chain reaction, Western blotting, and immunofluorescence microscopy. PFIC was diagnosed by clinical and laboratory findings. All patients could be assigned to PFIC-2 or PFIC-3 by the use of BSEP-and MDR3-specific antibodies and by MDR3 gene-sequencing. Whereas in all PFIC-2 patients, BSEP immunoreactivity was absent from the canalicular membrane, in three PFIC-3 livers, canalicular MDR3 immunoreactivity was detectable. Serum bile salts were elevated to 276 ؎ 233 and to 221 ؎ 109 mol/L in PFIC-2 and PFIC-3, respectively. Organic anion transporting polypeptide OATP1B1, OATP1B3, and MRP2 mRNA and protein levels were reduced, whereas sodium taurocholate cotransporting polypeptide (NTCP) was only reduced at the protein level, suggesting a posttranscriptional NTCP regulation. Whereas MRP3 mRNA and protein were not significantly altered, MRP4 messenger RNA and protein were significantly increased in PFIC. In conclusion, PFIC-2 may be reliably diagnosed by immunofluorescence, whereas the diagnosis of PFIC-3 requires gene-sequencing. Several mechanisms may contribute to elevated plasma bile salts in PFIC: reduced bile salt uptake via NTCP, OATP1B1, and OATP1B3, decreased BSEP-dependent secretion into bile, and increased transport back into plasma by MRP4. Upregulation of MRP4, but not of MRP3, might represent an important escape mechanism for bile salt extrusion in PFIC. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/ suppmat/index.html). (HEPATOLOGY 2005;41:1160-1172

show abstract

Changes in the expression and localization of hepatocellular transporters and radixin in primary biliary cirrhosis

Cited by 147 publications

References 31 publications

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

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

The apical conjugate efflux pump ABCC2 (MRP2)

Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis

Contact Info

Product

Resources

About