Caspase-12 mediates carbon tetrachloride-induced hepatocyte apoptosis in mice

AIM:To investigate the role of caspase-12 and its downstream targets in carbon tetrachloride(CCl4)-induced hepatocyte apoptosis.METHODS:The role of caspase-12 was determined by using caspase-12 knock-out(-/-)mice.CCl4(300μL/kg body weight)or vehicle(corn oil)was administered to caspase-12+/+or caspase-12-/-mice as a single intraperitoneal injection.The animals were sacrificed24 h after the CCl4 treatment.Blood was collected to evaluate liver function by the measurement of the activity of alanine aminotransferase.Liver samples were used for the measurements of reactive oxygen species using plasma malondialdehyde as biomarker,hepatocyte apoptosis was evaluated via terminal transferasemediated d UTP nick-end labeling and controlled by morphologic study,and cytochrome C release and caspase activations were measured by Western blotting.RESULTS:Administration of a low dose of CCl4resulted in hepatocyte apoptosis and acute liver injury in wild-type mice.CCl4 also induced the generation of reactive oxygen species and induction of endoplasmic reticulum stress in the liver followed by activations of caspase-12,-9 and-3 as well as release of small amounts of cytochrome C.However,in the CCl4-treated caspase-12-/-mice,activation of caspase-9 and-3 were significantly attenuated(P<0.05);no effect was seen in cytochrome C release.CCl4-induced apoptosis and liver damage was markedly reduced in caspase-12-/-mice compared to caspase-12+/+mice(P<0.05).The active form of caspase-8 was not detected in either caspase-12+/+or caspase-12-/-mice.There was no significant different in the formation of reactive oxygen species in the livers of caspase-12+/+and caspase-12-/-mice treated with CCl4.CONCLUSION:Caspase-12 plays a pivotal role in CCl4-induced hepatic apoptosis through the activation of the downstream effector caspase-3 directly and/or indirectly via capase-9 activation.

Cirrhosis complicating Shwachman-Diamond syndrome: A case report

BACKGROUND The features of Shwachman-Diamond syndrome (SDS) include exocrine pancreatic insufficiency, skeletal abnormalities and bone marrow dysfunction;an often overlooked feature is hepatic involvement. CASE SUMMARY We report a child who initially presented with failure to thrive and mildly elevated transaminase levels and was determined to have pancreatic insufficiency due to SDS. During follow-up he had persistently elevated transaminase levels and developed hepatosplenomegaly. An investigation was performed to determine the etiology of ongoing liver injury, including a liver biopsy which revealed hepatic cirrhosis. CONCLUSION Cirrhosis has rarely been reported with SDS. While many of the hepatic disorders associated with SDS improve with age, there are rare exceptions with serious implications for long-term outcome.

Evaluating the regulation of transporter proteins and P-glycoprotein in rats with cholestasis and its implication for digoxin clearance

BACKGROUND Cardiac and hepatic functionality are intertwined in a multifaceted relationship.Pathologic processes involving one may affect the other through a variety of mechanisms,including hemodynamic and membrane transport effects.AIM To better understand the effect of extrahepatic cholestasis on regulations of membrane transporters involving digoxin and its implication for digoxin clearance.METHODS Twelve adult rats were included in this study;baseline hepatic and renal laboratory values and digoxin pharmacokinetic(PK)studies were established before evenly dividing them into two groups to undergo bile duct ligation(BDL)or a sham procedure.After 7 d repeat digoxin PK studies were completed and tissue samples were taken to determine the expressions of cell membrane transport proteins by quantitative western blot and real-time polymerase chain reaction.Data were analyzed using SigmaStat 3.5.Means between pre-surgery and post-surgery in the same experimental group were compared by paired t-test,while independent t-test was employed to compare the means between sham and BDL groups.RESULTS Digoxin clearance was decreased and liver function,but not renal function,was impaired in BDL rats.BDL resulted in significant up-regulation of multidrug resistance 1 expression in the liver and kidney and its down-regulation in the small intestine.Organic anion transporting polypeptides(OATP)1A4 was up-regulated in the liver but down-regulated in intestine after BDL.OATP4C1 expression was markedly increased in the kidney following BDL.CONCLUSION The results suggest that cell membrane transporters of digoxin are regulated during extrahepatic cholestasis.These regulations are favorable for increasing digoxin excretion in the kidney and decreasing its absorption from the intestine to compensate for reduced digoxin clearance due to cholestasis.