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BackgroundTriggers and exacerbants of cirrhotic cardiomyopathy (CC) are poorly understood, limiting treatment options in patients with chronic liver diseases. Liver transplantation alone reverses some features of CC, but the physiology behind this effect has never been studied.AimsWe aimed to determine whether reversal of liver injury and fibrosis in mouse affects cardiac parameters. The second aim was to determine whether cardiomyopathy can be induced by specifically increasing systemic bile acid (BA) levels.Methods6-8 week old male C57BL6J mice were fed either chow (n = 5) or 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) (n = 10) for 3 weeks. At the end of 3 weeks, half the mice in the DDC fed group were randomized to chow (the reversed [REV] group). Serial ECHOs and electrocardiographic analysis was conducted weekly for 6 weeks followed by liver tissue and serum studies. Hearts were analysed for key components of function and cell signalling. Cardiac physiological and molecular parameters were similarly analysed in Abcb11(-/-) mice (n = 5/grp) fed 0.5% cholic acid supplemented diet for 1 week.ResultsMice in the REV group showed normalization of biochemical markers of liver injury with resolution of electrocardiographic and ECHO aberrations. Catecholamine resistance seen in DDC group resolved in the REV group. Cardiac recovery was accompanied by normalization of cardiac troponin-T2 as well as resolution of cardiac stress response at RNA level. Cardiovascular physiological and molecular parameters correlated with degree of cholanemia. Cardiomyopathy was reproduced in cholanemic BA fed Abcb11(-/-) mice.ConclusionsCardiomyopathy resolves with resolution of liver injury, is associated with cholanaemia, and can be induced by BA feeding.

A correction to the article "Gene-specific alterations of hepatic gene expression by ligand activation or hepatocyteselective inhibition of retinoid X receptor-α signalling during inflammation" that was published in the 2012 issue is presented.

Background & Aims Mammalian target of rapamycin and angiotensin-converting enzyme inhibition has been shown to have antifibrotic activity in models of liver fibrosis. The aim of our study was to determine the efficacy of rapamycin, everolimus, irbesartan and captopril, alone and in combination, as antifibrotic agents in the Mdr2 −/− model of cholestasis both in early injury and established disease. Methods Mdr2 −/− mice were treated for 4 weeks with vehicle, rapamycin (1 mg/kg) or everolimus (5 mg/kg) every second day or with captopril (30 mg/kg/day), irbesartan (10 mg/kg/day) or vehicle. Further groups of 3-week-old Mdr2 −/− mice were treated with rapamycin and irbesartan in combination (1 mg/kg/day and 10 mg/kg/day) or with rapamycin (2 mg/kg/day) for 4 weeks. Liver injury and fibrosis were compared between treated and untreated animals. Results There were no significant improvements in liver injury, histology, hepatic hydroxyproline or profibrogenic gene expression following treatment with rapamycin, everolimus, captopril or irbesartan at any time point studied. Likewise, there were no improvements in liver histology or profibrogenic gene expression following combination therapy or high-dose rapamycin treatment. Conclusions The antifibrotic effects of rapamycin, everolimus, captopril and irbesartan seen in other models of fibrosis were not replicated in the Mdr2 −/− model in this study. This highlights the clear need to test specific antifibrotic agents in a number of different animal models. We believe this animal model is ideal to study usefulness of antifibrotic agents in cholestatic liver disease because of the similarity in genetics and hepatic histopathology to human cholestatic liver disease. [ABSTRACT FROM AUTHOR]

Background Cholestasis is a common disease of the liver. Chronic cholestasis eventually leads to hepatic cirrhosis and fibrosis, and rodent chronic cholestasis models are used to study aspects of fibrosis and cirrhosis. Cholestasis-induced liver injury and fibrosis are associated with increased oxidative stress and inflammation. Few pharmacological therapies exist for treatment of cholestasis or cirrhosis, but it is known that humans with better nutritional intake are less likely to develop certain types of cirrhosis. E ugenia jambolana ( J amun) is a tropical berry fruit rich in antioxidant anthocyanin compounds. Aim As anthocyanins decrease cellular lipid peroxidation and oxidative stress, it was hypothesized that Jamun fruit extract ( JFE) administration could protect against cholestatic liver injury and inflammation in mice. Method Starting 24 h after sham or bile-duct ligation ( BDL) surgery, male C57Bl/6 mice were administered vehicle or JFE (100 mg/kg, po) for 10 days. Results Mice that underwent BDL had elevated serum ALT levels, which were reduced to 60% by JFE treatment. Likewise, BDL caused hepatic inflammation, macrophage infiltration, fibrosis and necrosis, all of which were largely improved by JFE. Interestingly, hepatoprotection was observed in JFE-treated BDL mice, despite suppressed transporter expression and increased hepatic bile acid concentrations. Conclusion Jamun fruit phytochemicals decreased hepatic inflammation and oxidative stress, and protected against hepatocellular injury in mice. Jamun warrants further investigation as a potential antioxidant/anti-inflammatory therapy not only to treat cholestasis but also other liver diseases with an inflammatory component. [ABSTRACT FROM AUTHOR]

Cholesterol available for bile secretion is controlled by a wide variety of proteins that mediate lipoprotein cholesterol uptake and cholesterol transport and metabolism in the liver. From a disease perspective, abnormalities in the transhepatic traffic of cholesterol from plasma into the bile may influence the risk of cholesterol gallstone formation. This review summarizes some recent progress in understanding the hepatic determinants of biliary cholesterol secretion and its potential pathogenic implications in cholesterol gallstone disease. This information together with new discoveries in this field may lead to improved risk evaluation, novel surrogate markers and earlier diagnosis, better preventive approaches and more effective pharmacological therapies for this prevalent human disease. [ABSTRACT FROM AUTHOR]

Background: Genetic variation in genes involved in steroid biosynthesis, metabolism and signal transduction have been suggested to play a role in gallstone disease. Methods: To elucidate the possible role of genetic variation in the estrogen receptors α and β ( ER-α, ER-β) and androgen receptor ( AR) genes in breast cancer risk, the −1174(TA) n, c.1092+3607(CA) n and c.172(CAG) n repeat polymorphisms of the three genes were studied. A case–control cohort of 99 patients with cholelithiasis and 179 controls were used. Results: No significant difference was observed in the frequency distribution of −1174(TA)0–26 in the ER-α gene between patients and controls, while a significant difference was observed in the frequency distribution of repeat polymorphism c.1092+3607(CA)5–27 and c.172(CAG)5–32 in the ER-β gene and AR gene, respectively ( P≤0.0001 and P=0.05, respectively). A significant difference was observed in the repeat genotype distribution (SS, SL, LL) in the (CA) n of the ER-β gene ( P<0.0001) and in the (CAG) n of the AR gene ( P≤0.0001). A significantly decreased odds ratio for cholelithiasis risk was observed in individuals having the SL and LL genotype for ER-β gene compared with SS genotype (OR=0.212; 95% CI 0.105–0.426; P<0.0001 and OR=0.042; 95% CI 0.018–0.097, respectively) and LL genotype for AR gene (OR=0.622; 95% CI 0.345–1.121; P=0.114 and OR=0.287; 95% CI 0.151–0.543, P<0.0001, respectively). This protective effect of SL and LL genotypes for ER-β and LL for AR gene remained evident ( P<0.0001 for all of them) even after adjustment for various risk factors. Conclusions: In conclusion an association for cholelithiasis risk between short alleles for both c.1092+3607(CA)5–27 and c.172(CAG)5–32 repeat polymorphisms of the ER-β and AR was found in individuals of Greek descent. [ABSTRACT FROM AUTHOR]