Hepatic Transport of Bile Salts

Kullak-Ublick, G; Stieger, Bruno; Hagenbuch, Bruno; Pj, Meier

doi:10.1055/s-2000-9426

Cited by 270 publications

(172 citation statements)

References 239 publications

(219 reference statements)

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“…25 Although Ntcp expression was normal in the livers of P0 PEX2 Ϫ/Ϫ mice (not shown), protein expression was significantly reduced in P10 untreated mutants and was further decreased with BA feeding (Fig. 10A).…”

Section: Resultsmentioning

confidence: 99%

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Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficientPEX2Zellweger mice

et al. 2007

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The marked deficiency of peroxisomal organelle assembly in the PEX2 ؊/؊ mouse model for Zellweger syndrome provides a unique opportunity to developmentally and biochemically characterize hepatic disease progression and bile acid products. The postnatal survival of homozygous mutants enabled us to evaluate the response to bile acid replenishment in this disease state. PEX2 mutant liver has severe but transient intrahepatic cholestasis that abates in the early postnatal period and progresses to steatohepatitis by postnatal day 36. We confirmed the expected reduction of mature C24 bile acids, accumulation of C27-bile acid intermediates, and low total bile acid level in liver and bile from these mutant mice. Treating the PEX2 ؊/؊ mice with bile acids prolonged postnatal survival, alleviated intrahepatic cholestasis and intestinal malabsorption, reduced C27-bile acid intermediate production, and prevented older mutants from developing severe steatohepatitis. However, this therapy exacerbated the degree of hepatic steatosis and worsened the already severe mitochondrial and cellular damage in peroxisome-deficient liver. Both untreated and bile acid-fed PEX2 ؊/؊ mice accumulated high levels of predominantly unconjugated bile acids in plasma because of altered expression of hepatocyte bile acid transporters. Significant amounts of unconjugated bile acids were also found in the liver and bile of PEX2 mutants, indicating a generalized defect in bile acid conjugation. Conclusion: Peroxisome deficiency widely disturbs bile acid homeostasis and hepatic functioning in mice, and the high sensitivity of the peroxisome-deficient liver to bile acid toxicity limits the effectiveness of bile acid therapy for preventing hepatic disease. (HEPATOLOGY 2007;45:982-997.)

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Section: Resultsmentioning

confidence: 99%

“…25 Northern blot analysis revealed that by P36 the major Oatp1 transporter was expressed in control mice but not in BA-fed PEX2 mutants (Fig. 12).…”

Section: Resultsmentioning

confidence: 99%

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficientPEX2Zellweger mice

et al. 2007

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“…A major driving force for bile formation is active secretion of bile salts, mediated by the adenosine triphosphate-dependent bile salt export pump, ABCB11. 16 Bile salt excretion induces an osmotic gradient that in turn causes the flow of water and accompanying solutes into the bile canalicular lumen. [17][18][19] Bile salts have detergent properties that enable them to solubilize membrane lipids and are present in millimolar concentrations in the canalicular lumen.…”

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confidence: 99%

Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport

et al. 2006

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Progressive familial intrahepatic cholestasis type 1 (PFIC1, Byler disease, OMIM 211600) is a severe inherited liver disease caused by mutations in ATP8B1. ATP8B1 is a member of the type 4 subfamily of P-type ATPases, which are phospholipid flippases. PFIC1 patients generally develop end-stage liver disease before the second decade of life. The disease is characterized by impaired biliary bile salt excretion, but the mechanism whereby impaired ATP8B1 function results in cholestasis is unclear. In a mouse model for PFIC1, we observed decreased resistance of the hepatocanalicular membrane to hydrophobic bile salts as evidenced by enhanced biliary recovery of phosphatidylserine, cholesterol, and ectoenzymes. In liver specimens from PFIC1 patients, but not in those from control subjects, ectoenzyme expression at the canalicular membrane was markedly deficient. In isolated mouse livers Atp8b1 deficiency impaired the transport of hydrophobic bile salts into bile. In conclusion, our study shows that Atp8b1 deficiency causes loss of canalicular phospholipid membrane asymmetry that in turn renders the canalicular membrane less resistant toward hydrophobic bile salts. The loss of phospholipid asymmetry may subsequently impair bile salt transport and cause cholestasis. Supplementary material for this article can be found on the HEPATOLOGY website (http://interscience.wiley.com/jpages/0270-9139/suppmat/ index.html). (HEPATOLOGY 2006;44:195-204.)

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“…Recent studies have described some of the genes involved in these transport processes; however, it is clear that many other genes and gene products remain to be identified and characterized (1)(2)(3)(4)(5)(6)(7).…”

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confidence: 99%

Functional Complementation between a Novel Mammalian Polygenic Transport Complex and an Evolutionarily Ancient Organic Solute Transporter, OSTα-OSTβ

Seward

Koh

Boyer

et al. 2003

Journal of Biological Chemistry

157

260

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These studies identify an organic solute transporter (OST) that is generated when two novel gene products are co-expressed, namely human OST␣ and OST␤ or mouse OST␣ and OST␤. The results also demonstrate that the mammalian proteins are functionally complemented by evolutionarily divergent Ost␣-Ost␤ proteins recently identified in the little skate, Raja erinacea, even though the latter exhibit only 25-41% predicted amino acid identity with the mammalian proteins. Human, mouse, and skate OST␣ proteins are predicted to contain seven transmembrane helices, whereas the OST␤ sequences are predicted to have a single transmembrane helix. Human OST␣-OST␤ and mouse Ost␣-Ost␤ cDNAs were cloned from liver mRNA, sequenced, expressed in Xenopus laevis oocytes, and tested for their ability to functionally complement the corresponding skate proteins by measuring transport of [ 3 H]estrone 3-sulfate. None of the proteins elicited a transport signal when expressed individually in oocytes; however, all nine OST␣-OST␤ combinations (i.e. OST␣-OST␤ pairs from human, mouse, or skate) generated robust estrone 3-sulfate transport activity. Transport was sodium-independent, saturable, and inhibited by other steroids and anionic drugs. Human and mouse OST␣-OST␤ also were able to mediate transport of taurocholate, digoxin, and prostaglandin E 2 but not of estradiol 17␤-D-glucuronide or p-aminohippurate. OST␣ and OST␤ were able to reach the oocyte plasma membrane when expressed either individually or in pairs, indicating that co-expression is not required for proper membrane targeting. Interestingly, OST␣ and OST␤ mRNAs were highly expressed and widely distributed in human tissues, with the highest levels occurring in the testis, colon, liver, small intestine, kidney, ovary, and adrenal gland.

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Hepatic Transport of Bile Salts

Cited by 270 publications

References 239 publications

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficientPEX2Zellweger mice

Bile acid treatment alters hepatic disease and bile acid transport in peroxisome-deficientPEX2Zellweger mice

Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport

Functional Complementation between a Novel Mammalian Polygenic Transport Complex and an Evolutionarily Ancient Organic Solute Transporter, OSTα-OSTβ

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