Effects of Ursodeoxycholic and Cholic Acid Feeding on Hepatocellular Transporter Expression in Mouse Liver

Fickert, Peter; Zollner, Gernot; Fuchsbichler, Andrea; Stumptner, Cornelia; Pojer, Christine; Zenz, Rainer; Lammert, Frank; Stieger, Bruno; Meier, Peter J.; Zatloukal, Kurt; Denk, Helmut; Trauner, Michael

doi:10.1053/gast.2001.25542

Cited by 249 publications

(208 citation statements)

References 58 publications

Supporting

Mentioning

186

Contrasting

Unclassified

Order By: Relevance

“…34 TUDCA is known to stimulate the expression of transporter proteins and their targeting and insertion into the canalicular membrane for biliary secretion in the liver. 20,21 In our study, treatment with TUDCA reverted Mrp2 protein expression to basal levels in obstructed animals. Remarkably, the inhibition of NO synthesis by treating the rats with SMT also caused a recovery in liver Mrp2 protein levels.…”

Section: Protein S-nitrosation During Cholestasissupporting

confidence: 57%

“…18,19 Taurine-conjugated ursodeoxycholic acid (TUDCA) is known to protect hepatocytes in cholestasis by stimulating the expression and membrane insertion of transporter proteins. 20,21 Therefore, we treated BDL rats with SMT, and TUDCA was used as the clinical comparator in these studies. Our results suggest that the inhibition of NO synthesis during induced cholestasis ameliorates hepatocellular injury, and that this therapeutic effect is in part mediated by the improvement of liver proficiency in maintaining SNO homeostasis.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Inhibition of nitric oxide synthesis during induced cholestasis ameliorates hepatocellular injury by facilitating S-nitrosothiol homeostasis

López‐Sánchez

Corrales

Barcos

et al. 2010

Laboratory Investigation

View full text Add to dashboard Cite

Cholestatic liver injury following extra-or intrahepatic bile duct obstruction causes nonparenchymal cell proliferation and matrix deposition leading to end-stage liver disease and cirrhosis. In cholestatic conditions, nitric oxide (NO) is mainly produced by a hepatocyte-inducible NO synthase (iNOS) as a result of enhanced inflow of endotoxins to the liver and also by accumulation of bile salts in hepatocytes and subsequent hepatocellular injury. This study was aimed to investigate the role of NO and S-nitrosothiol (SNO) homeostasis in the development of hepatocellular injury during cholestasis induced by bile duct ligation (BDL) in rats. Male Wistar rats (200-250 g) were divided into four groups (n ¼ 10 each), including sham-operated (SO), bile duct-ligated (BDL), tauroursodeoxycholic acid (TUDCA, 50 mg/kg) and S-methylisothiourea (SMT, 25 mg/kg) treated. After 7 days, BDL rats showed elevated serum levels of g-glutamiltranspeptidase, aspartate aminotransferase, alanine aminotransferase, LDH, and bilirubin, bile duct proliferation and fibrosis, compared with the SO group. TUDCA treatment did not significantly alter these parameters, but the iNOS inhibitor SMT ameliorated hepatocellular injury, as shown by lower levels of circulating hepatic enzymes and bilirubin, and a decreased grade of bile duct proliferation and fibrosis. Both TUDCA and SMT treatments reversed Mrp2 canalicular pump expression to control levels. However, only SMT treatment significantly lowered the increased levels of plasma NO and S-nitrosation (S-nitrosylation) of liver proteins in BDL rats. Moreover, BDL resulted in a reduction of the S-nitrosoglutathione reductase (GSNOR/Adh5) enzymatic activity and a downregulation of the GSNOR/Adh5 mRNA expression that was reverted by SMT, but not TUDCA, treatment. A total of 25 liver proteins, including S-adenosyl methionine synthetase, betainehomocysteine S-methyltransferase, Hsp90 and protein disulfide isomerase, were found to be S-nitrosated in BDL rats. In conclusion, the inhibition of NO production during induced cholestasis ameliorates hepatocellular injury. This effect is in part mediated by the improvement of cell proficiency in maintaining SNO homeostasis.

show abstract

Section: Protein S-nitrosation During Cholestasissupporting

confidence: 57%

mentioning

confidence: 99%

Inhibition of nitric oxide synthesis during induced cholestasis ameliorates hepatocellular injury by facilitating S-nitrosothiol homeostasis

López‐Sánchez

Corrales

Barcos

et al. 2010

Laboratory Investigation

View full text Add to dashboard Cite

show abstract

“…In addition, it has been shown to stimulate canalicular transport and biliary excretion enhancing bile flow and reducing the exposure time of biliary epithelium to toxic bile salts. 34 However, its choleretic action also increases biliary pressure, which has been shown to aggravate bile infarcts and hepatocyte necrosis in the homozygous Mdr2Ϫ/Ϫ mice. 15 Moreover, ursodeoxycholic acid also displays a toxic character, affecting mitochondrial activity.…”

Section: Discussionmentioning

confidence: 99%

Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation inMdr2+/− mice

et al. 2006

Self Cite

View full text Add to dashboard Cite

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

show abstract

“…The transcriptional regulation of canalicular transporter proteins by UDCA and cholic acid (CA) has recently been addressed. 23 In hepatocytes of mice fed a UDCA-or CAsupplemented diet, both UDCA and CA up-regulated Bsep and Mrp2 mRNA. Since this effect was not specific for UDCA, its role for the anticholestatic action of UDCA remains unclear.…”

Section: Stimulation Of Hepatobiliary Secretionmentioning

confidence: 96%

Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited

Paumgartner¹

2002

Hepatology

636

383

View full text Add to dashboard Cite

Effects of Ursodeoxycholic and Cholic Acid Feeding on Hepatocellular Transporter Expression in Mouse Liver

Cited by 249 publications

References 58 publications

Inhibition of nitric oxide synthesis during induced cholestasis ameliorates hepatocellular injury by facilitating S-nitrosothiol homeostasis

Inhibition of nitric oxide synthesis during induced cholestasis ameliorates hepatocellular injury by facilitating S-nitrosothiol homeostasis

Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation inMdr2+/− mice

Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited

Contact Info

Product

Resources

About