3-hydroxy-3-methylglutaryl–coenzyme a reductase inhibitors (statins) induce hepatic expression of the phospholipid translocase mdr2 in rats

Hooiveld, Guido; Vos, T. A.; Scheffer, George L.; Goor, Harry van; Koning, Henk; Bloks, Vincent W.; Loot, Annemarieke E.; Meijer, Dirk K. F.; Jansen, Petér L. M.; Kuipers, Folkert; Müller, Michael

doi:10.1016/s0016-5085(99)70462-2

Cited by 60 publications

(58 citation statements)

References 54 publications

(65 reference statements)

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“…41 Stimulation of pregnane X receptor/sterol X receptor reduces bilirubin and serum bile acid levels in humans and rodents. 31,42 Moreover, statins have been shown to stimulate biliary excretion of phospholipids 34,35 that may further protect bile ducts from immunomediated injury in PBC. 43,44 This may be explained by activation of the nuclear peroxisome proliferator-activated receptor-␣, 45 which is predicted to modulate biliary bile acid/phospholipid ratio via increased biliary phospholipid secretion and increased cholangiocellular reabsorption of biliary bile acids, 31,46 resulting in less aggressive bile.…”

Section: Discussionmentioning

confidence: 99%

“…31,32 Additional beneficial effects of statins in cholestasis could result from a stimulation of bile acid metabolism, detoxification, and transport, which are predicted to counteract bile acid toxicity. 33 Part of these statin effects could be explained by activation of nuclear receptors such as the pregnane X receptor/sterol X receptor and peroxisome proliferator-activated receptor-␣, 31,[34][35][36] because these nuclear receptors have been shown to regulate transport and metabolism of biliary constituents. 33 Thus, statins may be considered nuclear receptor-targeted agents that are already available for the treatment of liver disease.…”

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confidence: 99%

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Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid

et al. 2007

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Statin therapy may target both hypercholesterolemia and cholestasis in primary biliary cirrhosis (PBC). However, little is known about the efficacy and safety of statins in PBC. The aim of this single-center study was therefore to prospectively examine the effects of atorvastatin on serum markers of cholestasis, aminotransferases, and lipid and bile acid metabolism as well as inflammatory and immunological markers in patients with PBC. Fifteen patients with early-stage PBC and an incomplete biochemical response to ursodeoxycholic acid (UDCA) therapy (defined as alkaline phosphatase 1.5-fold above the upper limit of normal after 1 year) were treated with atorvastatin 10 mg/day, 20 mg/day, and 40 mg/day for 4 weeks, respectively. Serum levels of alkaline phosphatase increased during atorvastatin 20 mg and 40 mg (P < 0.05), whereas leucine aminopeptidase and ␥-glutamyltransferase remained unchanged. No statistical differences in overall serum ALT, AST, bilirubin, and IgM levels were observed. However, atorvastatin was discontinued in 1 out of 15 patients because of ALT 2-fold above baseline, and 2 patients showed ALT elevations 3-fold above the upper limit of normal at the end of the atorvastatin treatment period. Serum total cholesterol and low-density lipoprotein cholesterol levels decreased by 35% and 49%, respectively (P < 0.001). Precursors of cholesterol biosynthesis (lanosterol, desmosterol, lathosterol) showed a similar pattern. No changes in serum bile acid levels and composition were observed during treatment. Conclusion: Atorvastatin does not improve cholestasis in PBC patients with an incomplete biochemical response to UDCA but effectively reduces serum cholesterol levels. (HEPATOLOGY 2007;46:776-784.)

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid

et al. 2007

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“…10 Alternatively, the administration of fibrates, statins, or peroxisome proliferators, which all have been shown to induce biliary phospholipid secretion by the induction of Mdr2, making bile less toxic, might pose a therapeutic approach to prevent bile duct complications after OLT . [35][36][37] However, these compounds may induce other hepatic injury and have considerable side effects. 38 In conclusion, our data indicate that toxic bile composition, because of a high biliary bile salt/phospholipid ratio, acts synergistically to ischemia/reperfusion injury in the origin of bile duct injury after OLT.…”

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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“…As a vehicle, 100 L of DMSO (for comparison in the PB and PCN group) or corn oil (for comparison in the TCPOBOP group) were applied in the same manner. Atorvastatin as a less potent-but for the treatment of human cholestatic liver diseases, clinically more relevant [11][12][13] -PXR agonist was fed as a 0.1% enriched standard diet (wt/wt) for 7 days 14 and compared with control mice fed a standard diet. Twenty-four hours after the last dose, the livers and kidneys were excised under general anesthesia (400 mg avertin/kg body weight intraperitoneally).…”

Section: Methodsmentioning

confidence: 99%

CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice†

et al. 2005

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3-hydroxy-3-methylglutaryl–coenzyme a reductase inhibitors (statins) induce hepatic expression of the phospholipid translocase mdr2 in rats

Abstract: Statins increase expression of mdr2 and mdr1b in rats, revealing a novel effect of these commonly used drugs.

Cited by 60 publications

References 54 publications

Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid

Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid

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

CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice†

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