Regulation of the multidrug resistance protein 2 in the rat liver by lipopolysaccharide and dexamethasone

Kubitz, Ralf; Wettstein, Matthias; Warskulat, Ulrich; Häussinger, Dieter

doi:10.1016/s0016-5085(99)70138-1

Cited by 223 publications

(224 citation statements)

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“…Maintenance of bile salt homeostasis is important because bile salts exert many biological effects in liver and extrahepatic organs. 27 Long-term adaptation of bile salt transporters involves changes at the messenger RNA (mRNA) and protein levels, 28 whereas covalent modifications (e.g., phosphorylation), 29 substrate availability, 30 or rapid endo-and exocytosis of transporter-containing vesicles 19,31 represent modalities of short-term regulation. Current concepts assume mechanisms that would limit intracellular accumulation of potentially toxic bile salts under cholestatic conditions.…”

Section: Discussionmentioning

confidence: 99%

“…The study protocol was approved by the local authorities. Livers of male Wistar rats (150 g) were perfused in a nonrecirculating system as described 19 with a flow rate of 4 mL/g liver/min, where liver weight was estimated to be 4% of body weight. TC was present at a concentration of 100 lmol/L in the influent throughout the experiment in order to saturate bile salt transport.…”

Section: Methodsmentioning

confidence: 99%

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Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

et al. 2012

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The sodium taurocholate cotransporting polypeptide (Ntcp) is the major bile salt uptake transporter at the sinusoidal membrane of hepatocytes. Short-term feedback regulation of Ntcp by primary bile salts has not yet been investigated in vivo. Subcellular localization of Ntcp was analyzed in Ntcp-transfected HepG2-cells by flow cytometry and in immunofluorescence images from tissue sections by a new automated image analysis method. Net bile salt uptake was investigated in perfused rat liver by a pulse chase technique. In Flag-Ntcp-EGFP (enhanced green fluorescent protein) expressing HepG2-cells, taurochenodeoxycholate (TCDC), but not taurocholate (TC), induced endocytosis of Ntcp. TCDC, but not TC, caused significant internalization of Ntcp in perfused rat livers, as shown by an increase in intracellular Ntcp immunoreactivity, whereas Bsep distribution remained unchanged. These results correlate with functional studies. Rat livers were continuously perfused with 100 mu mol/L of TC. 25 mu mol/L of TCDC, taurodeoxycholate (TDC), tauroursodeoxycholate (TUDC), or TC were added for 30 minutes, washed out, followed by a pulse of (3)[H]-TC. TCDC, but not TDC, TUDC, or TC significantly increased the amount of (3)[H]-TC in the effluent, indicating a reduced sinusoidal net TC uptake. This effect was sensitive to chelerythrine (protein kinase C inhibitor) and cypermethrin (protein phosphatase 2B inhibitor). Phosphoinositide 3-kinase (PI3K) inhibitors had an additive effect, whereas Erk1/2 (extracellular signal activated kinase 1/2), p38MAPK, protein phosphatase 1/2A (PP1/2A), and reactive oxygen species (ROS) were not involved. Conclusion: TCDC regulates bile salt transport at the sinusoidal membrane by protein kinase C-and protein phosphatase 2B-mediated retrieval of Ntcp from the plasma membrane. During increased portal bile salt load this mechanism may adjust bile salt uptake along the acinus and protect periportal hepatocytes from harmful bile salt concentrations

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

et al. 2012

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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].…”

Section: Transcriptional and Posttranscriptional Regulation Of Abcc2mentioning

confidence: 99%

“…Insertion of Abcc2 into the canalicular membrane of rat hepatocytes may depend on the lipid kinase phosphoinositide 3-kinase [116], on protein kinase C [7], or on cyclic AMP [142]. Retrieval of rat Abcc2 transporter molecules from the canalicular membrane into the hepatocyte has been detected under different cholestatic conditions [119,136,169], after phalloidin treatment [143], after cytokine stimulation [29,99], and under hyperosmolar conditions [29,97]. 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.…”

Section: Transcriptional and Posttranscriptional Regulation Of Abcc2mentioning

confidence: 99%

The apical conjugate efflux pump ABCC2 (MRP2)

Nies

Keppler

2006

Pflugers Arch - Eur J Physiol

357

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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“…On a long-term scale, MRP2 expression is modulated by ethinyl oestradiol, chemotherapeutic agents, barbiturates and bile-duct ligation [10][11][12][13], but nothing is known about the role of osmolarity on MRP2 expression. Endotoxin downregulates MRP2 at the protein and mRNA levels [13], in addition to a short-term retrieval of MRP2 from the canalicular membrane [14]. Cholestasis induced by endotoxin is counteracted by glucocorticoids [14,15].…”

Section: Introductionmentioning

confidence: 99%

Dexamethasone- and osmolarity-dependent expression of the multidrug-resistance protein 2 in cultured rat hepatocytes1

Kubitz

Warskulat

Schmitt

et al. 1999

Biochemical Journal

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Expression of the conjugate export pump multidrug-resistance protein 2 (MRP2) in liver is regulated by endotoxin and antitumour agents. This paper reports on the effects of dexamethasone and osmolarity on MRP2 expression. MRP2 expression was studied at the protein, mRNA, immunocytochemical and functional levels in cultured rat hepatocytes. Protein and mRNA expression of MRP2 in rat hepatocytes 24 and 48 h after isolation were largely dependent on the presence of dexamethasone (100 nmol\l) in the culture medium. MRP2 was localized at the pseudocanalicular membrane and increased expression of MRP2 was accompanied by a widening of the pseudocanaliculi. In presence of dexamethasone, hypo-osmolarity (205 mosmol\l) led to a strong induction of MRP2 mRNA

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Regulation of the multidrug resistance protein 2 in the rat liver by lipopolysaccharide and dexamethasone

Cited by 223 publications

References 30 publications

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

Short-term feedback regulation of bile salt uptake by bile salts in rodent liver

The apical conjugate efflux pump ABCC2 (MRP2)

Dexamethasone- and osmolarity-dependent expression of the multidrug-resistance protein 2 in cultured rat hepatocytes1

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