Adaptive regulation of bile salt transporters in kidney and liver in obstructive cholestasis in the rat

Lee, John; Azzaroli, Francesco; Wang, Lin; Soroka, Carol J.; Gigliozzi, Alessandro; Setchell, Kenneth D.R.; Kramer, Werner; Boyer, James L.

doi:10.1053/gast.2001.29608

Cited by 149 publications

(142 citation statements)

References 40 publications

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“…Although Mrp2 protein was increased significantly in the kidneys of Mrp4Ϫ/Ϫ mice, it did not reach statistical significance in wild-type mice after CBDL, unlike in the rat 30,31 (Fig. 5B-C).…”

Section: Cbdl Results In More Livermentioning

confidence: 88%

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 Livermentioning

confidence: 88%

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

et al. 2006

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“…[ 3 H(G)]Taurocholic acid (2 Ci/mmol), [6, H(N) estrone 3-sulfate (46 Ci/mmol), and [1,2,6, Northern Blot Analysis. DNA probes were generated via polymerase chain reaction (PCR) from linearized polyA vectors (351-to 402-bp probes), and the resulting amplicons were sequenced.…”

Section: Methodsmentioning

confidence: 99%

“…2 In the bile duct-obstructed rat, downregulation of renal Asbt facilitates renal excretion of bile acids. 6 In contrast to the apical uptake step, the mechanism for sterol export across the basolateral membrane of these cells is not well defined. However, a recent study demonstrated that ileal basolateral bile acid export may be mediated by the Ost␣-Ost␤ heteromeric transporter, 7 a transporter that was initially identified in the liver of the little skate (Leucoraja erinacea).…”

mentioning

confidence: 99%

OSTα‐OSTβ

et al. 2005

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“…Down-regulation of Abcc2 mRNA and Abcc2 protein in rat liver after experimental cholestasis induced either by bile duct ligation or endotoxin treatment [99,169,178] may be explained by an upregulation of the inflammatory cytokine interleukin-1β, which in turn down-regulates the heterodimeric retinoic acid receptor α/RXRα, leading to downregulation of Abcc2 promoter activity [27]. Interestingly, Abcc2 expression in the kidney is preserved or up-regulated during cholestasis [27,103]. In humans, ABCC2 mRNA levels were reduced in livers from patients with primary sclerosing cholangitis [130] or with obstructive cholestasis [153].…”

Section: Transcriptional and Posttranscriptional Regulation Of Abcc2mentioning

confidence: 99%

The apical conjugate efflux pump ABCC2 (MRP2)

Nies

Keppler

2006

Pflugers Arch - Eur J Physiol

358

255

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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

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Adaptive regulation of bile salt transporters in kidney and liver in obstructive cholestasis in the rat

Cited by 149 publications

References 40 publications

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

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

OSTα‐OSTβ

The apical conjugate efflux pump ABCC2 (MRP2)

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