Hepatobiliary Transporter Expression in Intercellular Adhesion Molecule 1 Knockout and Fas Receptor-Deficient Mice after Common Bile Duct Ligation Is Independent of the Degree of Inflammation and Oxidative Stress

Abstract

ABSTRACT:Liver injury in intercellular adhesion molecule 1 knockout (ICAM ؊/؊ ) and Fas receptor-deficient (lpr) mice is markedly reduced after common bile duct ligation (CBDL) due to significantly reduced inflammation and oxidative stress. Liver injury in CBDL rodents is counteracted by adaptive hepatobiliary transporter induction. Since hepatobiliary transporter expression in obstructive cholestasis may be regulated not only by accumulating bile acids but also by inflammatory mediators and oxidative stress, we hypothesized that differences in the inflammatory response may affect hepatobiliary transporter expression in CBDL, which would contribute to reduced liver injury. Therefore, expression of major hepatobiliary transporters (Ntcp, Bsep, Mrp2-4, Ost␣/␤) was determined by Taqman

Elevated copper impairs hepatic nuclear receptor function in Wilson’s disease

“…In cholestatic mouse models such as bile duct ligation, decreased nuclear receptor activity has been attributed to inflammation that resulted in decreased nuclear receptor expression (43,44,48,49). Activation of hepatic stellate cells and inflammatory pathways have been specifically associated with decreased RXR expression (21)(22)(23)(24)(25). In accord with this, we observed decreased expression of Rxr mRNA in the Atp7b -/-livers and in the pediatric WD/no trientine and PFIC samples, but not in the adult patient samples.…”

“…and pathways, such as the inflammatory pathway, that decrease RXR expression (21)(22)(23)(24)(25). LRH-1 and HNF4α are orphan nuclear receptors that are essential for the regulation of bile acid synthetic genes, such as Cyp7a1 and Cyp8b1.…”

Farnesoid X Receptor Critically Determines the Fibrotic Response in Mice but Is Expressed to a Low Extent in Human Hepatic Stellate Cells and Periductal Myofibroblasts

“…Moreover, collagen 1a2 mRNA expression in FXR Ϫ/Ϫ mice was significantly lower despite significantly lower Shp expression compared with wild-type controls (Figure 3, D and E Figure S1 at http://ajp.amjpathol.org), we next compared the levels of protoporphyrin IX in serum, bile, urine, and liver in FXR Ϫ/Ϫ and wild-type mice. 36 Hepatic protoporphyrin IX content was significantly lower in DDC-intoxicated FXR Ϫ/Ϫ mouse livers compared with wild-type (see Supplemental Figure S4 at http://ajp.amjpathol.org), but no differences in serum and urine were observed (not shown). To rule out increased biliary elimination of protoporphyrin IX in FXR Ϫ/Ϫ mice we determined the biliary protoporphyrin IX output in both genotypes.…”

“…DDC-fed wild-type mice developed sclerosing cholangitis of the onion skin-type (see Supplemental Figure S1 at http://ajp.amjpathol.org) in line with findings previously reported in detail. 36 These morphological alterations where accompanied by a consistent increase in serum ALT levels as an indicator of hepatocyte injury (Table 3). In contrast, cholangitis was significantly abrogated in FXR Ϫ/Ϫ mice receiving DDC (see Supplemental Figure S1 at http://ajp.amjpathol.org).…”

The Pharmacokinetics of Silymarin Is Altered in Patients with Hepatitis C Virus and Nonalcoholic Fatty Liver Disease and Correlates with Plasma Caspase-3/7 Activity

“…In contrast to caspase-3/7 activity, plasma levels of 8-isoprostane F 2␣ , IL-6, and serum ALT values did not correlate with AUC 0 -24h for sum silymarin conjugates. Altered hepatic expression of biliary transporters was shown to be independent of the inflammation and oxidative stress associated with bile duct ligation (Wagner et al, 2005). Therefore, other components of disease activity, perhaps related to the development of cirrhosis, may account for the association between caspase-3/7 activity and altered disposition of silymarin conjugates, which was most apparent in the HCV cirrhotic cohort.…”