Regulation of MDR2 P-glycoprotein expression by bile salts

Frijters, C.M.G.; Ottenhoff, Roelof; Wijland, M.J.A. van; Nieuwkerk, C. van; Groen, A.K.; Elferink, Ronald P.J. Oude

doi:10.1016/0270-9139(95)95012-5

Cited by 6 publications

(6 citation statements)

References 34 publications

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“…5). Similar to the present finding in mice, Mdr2, as well as biliary concentration and excretion of phospholipids, also increases in rats 48 h after partial hepatectomy (57,74), likely in response to BA-activated FXR signaling (25,34,52). In addition, enhanced phospholipid synthesis in the remnant liver may also contribute to this protection (24).…”

Section: Discussionsupporting

confidence: 87%

Role of hepatic transporters in prevention of bile acid toxicity after partial hepatectomy in mice

Csanaky¹,

Aleksunes²,

Tanaka³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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The enterohepatic recirculation of bile acids (BAs) is important in several physiological processes. Although there has been considerable research on liver regeneration after two-thirds partial hepatectomy (PHx), little is known about how the liver protects itself against BA toxicity during regeneration. In this study, various BAs in plasma and liver, the composition of micelle-forming bile constituents, as well as gene expression of the main hepatobiliary transporters were quantified in sham-operated and PHx mice 24 and 48 h after surgery. PHx did not influence the hepatic concentrations of taurine-conjugated BAs (T-BA) but increased the concentration of glycine-conjugated (G-BA) and unconjugated BAs. Total BA excretion (microg x min(-1) x g liver wt(-1)) increased 2.4-fold and was accompanied by a 55% increase in bile flow after PHx. The plasma concentrations of T-BAs (402-fold), G-BAs (17-fold), and unconjugated BAs (500-fold) increased. The mRNA and protein levels of the BA uptake transporter Ntcp were unchanged after PHx, whereas the canalicular Bsep protein increased twofold at 48 h. The basolateral efflux transporter Mrp3 was induced at the mRNA (2.6-fold) and protein (3.1-fold) levels after PHx, which may contribute to elevated plasma BA and bilirubin levels. Biliary phospholipid excretion was nearly doubled in PHx mice, most likely owing to increased mRNA expression of the phospholipid transporter, Mdr2. In conclusion, the remnant liver after PHx excretes 2.5-fold more BAs and three times more phospholipids per gram liver than the sham-operated mouse liver. Upregulation of phospholipid transport may be important in protecting the biliary tract from BA toxicity during PHx.

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Section: Discussionsupporting

confidence: 87%

Role of hepatic transporters in prevention of bile acid toxicity after partial hepatectomy in mice

Csanaky¹,

Aleksunes²,

Tanaka³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…It has been established that Abcb4 expression in rodents is induced by bile salts [30,31]. Interestingly, this induction occurred with cholate feeding but not with ursodeoxycholate (UDCA) feeding.…”

Section: Regulation Of Abcb4 Expressionmentioning

confidence: 98%

Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein)

Elferink

Paulusma

2006

Pflugers Arch - Eur J Physiol

250

197

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Like several other ATP-binding cassette (ABC) transporters, ABCB4 is a lipid translocator. It translocates phosphatidylcholine (PC) from the inner to the outer leaflet of the canalicular membrane of the hepatocyte. Its function is quite crucial as evidenced by a severe liver disease, progressive familial intrahepatic cholestasis type 3, which develops in persons with ABCB4 deficiency. Translocation of PC makes the phospholipid available for extraction into the canalicular lumen by bile salts. The primary function of biliary phospholipid excretion is to protect the membranes of cells facing the biliary tree against these bile salts: the uptake of PC in bile salt micelles reduces the detergent activity of these micelles. In this review, we will discuss the functional aspects of ABCB4 and the regulation of its expression. Furthermore, we will describe the clinical and biochemical consequences of complete and partial deficiency of ABCB4 function.

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“…T␤MCA infusion rates were 150, 300, and 450 nmol/min, each for 30 min, followed by 600 nmol/min for 60 min. Infusion rates and concentrations of T␤MCA were similar to previously reported infusion experiments with tauroursodexoycholic acid (Pemt Ϫ/Ϫ mice) (44) and similar to others with other BS described in literature (13,31,35). Body temperature was stabilized during bile collection using a humidified incubator.…”

Section: Methodsmentioning

confidence: 71%

“…Bsep inactivation changes biliary BS composition, least effecting the secretion of the hydrophilic muricholic acid. It has been demonstrated that hydrophobic BS can induce hepatic mRNA expression of Mdr2 in mice via the nuclear receptor Fxr (8,13). Thus it could be that accumulated intrahepatocytic BS, directly or indirectly, induce the expression of canalicular transporters in Bsep Ϫ/Ϫ mice via Fxr or other nuclear receptors (12,36,37).…”

Section: Bs Stimulate Biliary Secretion Of Biliary Lipids (Pl and Ch)mentioning

confidence: 96%

The mechanism of increased biliary lipid secretion in mice with genetic inactivation of bile salt export pump

Gooijert

Havinga

Wolters

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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Human bile salt export pump (BSEP) mutations underlie progressive familial intrahepatic cholestasis type 2 (PFIC2). In the PFIC2 animal model, Bsep(-/-) mice, biliary secretion of bile salts (BS) is decreased, but that of phospholipids (PL) and cholesterol (CH) is increased. Under physiological conditions, the biliary secretion of PL and CH is positively related ("coupled") to that of BS. We aimed to elucidate the mechanism of increased biliary lipid secretion in Bsep(-/-) mice. The secretion of the BS tauro-β-muricholic acid (TβMCA) is relatively preserved in Bsep(-/-) mice. We infused Bsep(-/-) and Bsep(+/+) (control) mice with TβMCA in stepwise increasing dosages (150-600 nmol/min) and determined biliary bile flow, BS, PL, and CH secretion. mRNA and protein expression of relevant canalicular transporters was analyzed in livers from noninfused Bsep(-/-) and control mice. TβMCA infusion increased BS secretion in both Bsep(-/-) and control mice. The secreted PL or CH amount per BS, i.e., the "coupling," was continuously two- to threefold higher in Bsep(-/-) mice (P < 0.05). Hepatic mRNA expression of canalicular lipid transporters Mdr2, Abcg5, and Abcg8 was 45-55% higher in Bsep(-/-) mice (Abcg5; P < 0.05), as was canalicular Mdr2 and Abcg5 protein expression. Potential other explanations for the increased coupling of the biliary secretion of PL and CH to that of BS in Bsep(-/-) mice could be excluded. We conclude that the mechanism of increased biliary lipid secretion in Bsep(-/-) mice is based on increased expression of the responsible canalicular transporter proteins.

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Regulation of MDR2 P-glycoprotein expression by bile salts

Cited by 6 publications

References 34 publications

Role of hepatic transporters in prevention of bile acid toxicity after partial hepatectomy in mice

Role of hepatic transporters in prevention of bile acid toxicity after partial hepatectomy in mice

Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein)

The mechanism of increased biliary lipid secretion in mice with genetic inactivation of bile salt export pump

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