Influence of bile salts on hepatic mdr2 P-glycoprotein expression

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

doi:10.1016/0065-2571(95)00019-4

Cited by 19 publications

(12 citation statements)

References 31 publications

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“…[30][31][32] The induction of Mdr2 gene expression is in line with the function of biliary phospholipids to inactivate the detergent action of bile salts. 33 However, biliary phospholipid concentration was unchanged in Mdr2ϩ/Ϫ liver grafts.…”

Section: Discussionmentioning

confidence: 99%

Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2 +/− mice

et al. 2006

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Intrahepatic bile duct strictures are a serious complication after orthotopic liver transplantation (OLT). We examined the role of endogenous bile salt toxicity in the pathogenesis of bile duct injury after OLT. Livers from wild-type mice and mice heterozygous for disruption of the multidrug resistance 2 Mdr2 gene (Mdr2؉/؊) were transplanted into wild-type recipient mice. Mdr2؉/؊ mice secrete only 50% of the normal amount of phospholipids into their bile, leading to an abnormally high bile salt/phospholipid ratio. In contrast to homozygous Mdr2 ؊/؊ mice, the Mdr2؉/؊ mice have normal liver histology and function under normal conditions. Two weeks after OLT, bile duct injury and cholestasis were assessed by light and electron microscopy, as well as through molecular and biochemical markers. There were no signs of bile duct injury or intrahepatic cholestasis in liver grafts from wild-type donors. Liver grafts from Mdr2؉/؊ donors, however, had enlarged portal tracts with cellular damage, ductular proliferation, biliostasis, and a dense inflammatory infiltrate after OLT. Parallel to this observation, recipients of Mdr2؉/؊ livers had significantly higher serum transaminases, alkaline phosphatase, total bilirubin, and bile salt levels, as compared with recipients of wild-type livers. In addition, hepatic bile transporter expression was compatible with the biochemical and histological cholestatic profile found in Mdr2؉/؊ grafts after OLT. In conclusion, toxic bile composition, due to a high biliary bile salt/phospholipid ratio, acted synergistically with cold ischemia in the pathogenesis of bile duct injury after transplantation. (HEPATOLOGY 2006;43:1022-1031

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Section: Discussionmentioning

confidence: 99%

Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2 +/− mice

et al. 2006

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“…Contents of cholesterol, phospholipid, and triglyceride in liver tissue were determined after lipid extraction as described previously (41). Biliary bile salt, cholesterol, and phospholipid concentrations were determined as described previously (42,43). Biliary phospholipid species were analyzed by TLC as described by Smit et al (44).…”

Section: Methodsmentioning

confidence: 99%

Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL

Groen¹,

Bloks²,

Bandsma³

et al. 2001

J. Clin. Invest.

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The ABC transporter ABCA1 regulates HDL levels and is considered to control the first step of reverse cholesterol transport from the periphery to the liver. To test this concept, we studied the effect of ABCA1 deficiency on hepatic metabolism and hepatobiliary flux of cholesterol in mice. Hepatic lipid contents and biliary secretion rates were determined in Abca1 -/-, Abca1 +/-, and Abca1 +/+ mice with a DBA background that were fed either standard chow or a high-fat, high-cholesterol diet. Hepatic cholesterol and phospholipid contents in Abca1 -/-mice were indistinguishable from those in Abca1 +/-and Abca1 +/+ mice on both diets. In spite of the absence of HDL, biliary secretion rates of cholesterol, bile salts, and phospholipid were unimpaired in Abca1 -/-mice. Neither the hepatic expression levels of genes controlling key steps in cholesterol metabolism nor the contribution of de novo synthesis to biliary cholesterol and bile salts were affected by Abca genotype. Finally, fecal excretion of neutral and acidic sterols was similar in all groups. We conclude that plasma HDL levels and ABCA1 activity do not control net cholesterol transport from the periphery via the liver into the bile, indicating that the importance of HDL in reverse cholesterol transport requires re-evaluation.

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“…23 Biliary cholesterol, bile salt, and phospholipids from bile were measured by fluorescent methods as described previously. 24 Cholesterol and triglycerides in plasma were determined using colorimetric enzymatic kits from Biolabo (Maizy, France). Plasma cholesterol concentrations in the main lipoprotein classes were determined in a pool of plasma of each group (5 mice) separated by high-performance gel filtration chromatography as described before.…”

Section: Analytic Proceduresmentioning

confidence: 99%

Inhibition of Glycosphingolipid Synthesis Induces a Profound Reduction of Plasma Cholesterol and Inhibits Atherosclerosis Development in APOE*3 Leiden and Low-Density Lipoprotein Receptor−/− Mice

Bietrix

Lombardo

Roomen

et al. 2010

ATVB

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Objective-The iminosugar N-(5Ј-adamantane-1Ј-yl-methoxy)-pentyl-1-deoxynoijirimycin (AMP-DNM), an inhibitor of the enzyme glucosylceramide synthase catalyzing glycosphingolipid (GSL) biosynthesis, ameliorates diabetes and reduces liver steatosis in ob/ob mice. Because an accumulation of sphingolipids, including sphingomyelin and GSLs, has been reported in atherosclerotic lesions in animal models and in humans, the objective of this study was to determine whether AMP-DNM also exerts beneficial effects on the development of atherosclerosis. Methods and Results-APOE*3 Leiden mice, maintained on a high-cholesterol diet, were treated for up to 18 weeks with AMP-DNM. The iminosugar prevented hyperlipidemia, generated a less atherogenic lipid profile, and induced a dramatic reduction in the development of atherosclerotic lesions. At the highest dose, no lesions were detectable. The effect of AMP-DNM was associated with a decrease in liver cholesterol, an increase in bile secretion, and enhanced excretion of cholesterol in the feces. Similar effects of AMP-DNM were observed in mice deficient for the low-density lipoprotein receptor. Conclusion-By

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Influence of bile salts on hepatic mdr2 P-glycoprotein expression

Cited by 19 publications

References 31 publications

Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2 +/− mice

Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2 +/− mice

Hepatobiliary cholesterol transport is not impaired in Abca1-null mice lacking HDL

Inhibition of Glycosphingolipid Synthesis Induces a Profound Reduction of Plasma Cholesterol and Inhibits Atherosclerosis Development in APOE*3 Leiden and Low-Density Lipoprotein Receptor−/− Mice

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