Kazutaka Tanabe

Necrostatin‐1 protects against reactive oxygen species (ROS)‐induced hepatotoxicity in acetaminophen‐induced acute liver failure

Excessive acetaminophen (APAP) use is one of the most common causes of acute liver failure. Various types of cell death in the damaged liver are linked to APAP‐induced hepatotoxicity, and, of these, necrotic cell death of hepatocytes has been shown to be involved in disease pathogenesis. Until recently, necrosis was commonly considered to be a random and unregulated form of cell death; however, recent studies have identified a previously unknown form of programmed necrosis called receptor‐interacting protein kinase (RIPK)‐dependent necrosis (or necroptosis), which is controlled by the kinases RIPK1 and RIPK3. Although RIPK‐dependent necrosis has been implicated in a variety of disease states, including atherosclerosis, myocardial organ damage, stroke, ischemia–reperfusion injury, pancreatitis, and inflammatory bowel disease. However its involvement in APAP‐induced hepatocyte necrosis remains elusive. Here, we showed that RIPK1 phosphorylation, which is a hallmark of RIPK‐dependent necrosis, was induced by APAP, and the expression pattern of RIPK1 and RIPK3 in the liver overlapped with that of CYP2E1, whose activity around the central vein area has been demonstrated to be critical for the development of APAP‐induced hepatic injury. Moreover, a RIPK1 inhibitor ameliorated APAP‐induced hepatotoxicity in an animal model, which was underscored by significant suppression of the release of hepatic enzymes and cytokine expression levels. RIPK1 inhibition decreased reactive oxygen species levels produced in APAP‐injured hepatocytes, whereas CYP2E1 expression and the depletion rate of total glutathione were unaffected. Of note, RIPK1 inhibition also conferred resistance to oxidative stress in hepatocytes. These data collectively demonstrated a RIPK‐dependent necrotic mechanism operates in the APAP‐injured liver and inhibition of this pathway may be beneficial for APAP‐induced fulminant hepatic failure.

Attenuation of steatohepatitis, fibrosis, and carcinogenesis in mice fed a methionine-choline deficient diet by CCAAT/enhancer-binding protein homologous protein deficiency.

Hepatic steatosis is a metabolic liver disease with the potential to progress to steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The aim of this study was to investigate the impact of CCAAT/enhancer‐binding protein homologous protein (CHOP) deficiency in the development of steatosis‐associated progression of HCC.

Effects of oral intake of hydrogen water on liver fibrogenesis in mice

Liver fibrosis is the universal consequence of chronic liver diseases. Sustained hepatocyte injury initiates an inflammatory response, thereby activating hepatic stellate cells, the principal fibrogenic cells in the liver. Reactive oxygen species are involved in liver injury and are a promising target for treating liver fibrosis. Hydrogen water is reported to have potential as a therapeutic tool for reactive oxygen species‐associated disorders. This study aimed to investigate the effects of hydrogen water on liver fibrogenesis and the mechanisms underlying these effects.

Effect of olprinone on liver microstructure in rat partial liver transplantation

BACKGROUND Donor safety is a major concern in living-donor liver transplantation. However, partial grafts do not meet the functional demands of recipients and lead to small-for-size syndrome (SFSS). In a previous study, we showed that olprinone (OLP), a selective phosphodiesterase ІІІ inhibitor, up-regulates endothelial nitric oxide synthase level in the liver and attenuates shear stress, sinusoidal endothelial cell injury, and hepatocyte apoptosis after excessive liver resection in a rat model. We aimed to examine whether OLP treatment has beneficial effects on SFSS in a rat model of partial liver transplantation (PLT). METHODS We performed experiments in a rat model of 30% PLT. In the OLP group, we inserted an osmotic pump with OLP into the peritoneal cavity 48 h before liver graft sampling. Recipient rats were not treated with OLP. We examined the liver microstructure by electron microscopy and biochemical examination, and determined the 7-d survival of recipients. RESULTS In the OLP group 1 h after PLT, the sinusoidal endothelial cells of the liver were well preserved and we observed few vacuolar structures in hepatocytes. The total serum bilirubin level 1 wk after PLT tended to be lower in the OLP group than in the controls, and the liver microstructures were also well preserved in the OLP group. The probability of survival in the OLP group (100%; 14 of 14 rats) was significantly higher than that in the control group (75%; 15 of 20 rats). CONCLUSIONS Olprinone treatment was demonstrated to have therapeutic potential to overcome SFSS.

Usefulness of Mac-2 Binding Protein Glycosylation Isomer for Prediction of Posthepatectomy Liver Failure in Patients With Hepatocellular Carcinoma.

Objective: The aim of this study was to evaluate the usefulness of the Mac-2 binding protein glycosylation isomer (M2BPGi) for the prediction of posthepatectomy liver failure (PHLF) in hepatocellular carcinoma (HCC) patients. Summary Background Data: M2BPGi is a novel serum marker of liver fibrosis. The usefulness of M2BPGi for the prediction of PHLF has not been evaluated. Methods: Clinicopathological data were analyzed in 138 HCC patients who underwent liver resection between August 2011 and November 2014. PHLF was evaluated according to the definition of the International Study Group of Liver Surgery. Performance of preoperative parameters in predicting PHLF was determined using receiver operating characteristic (ROC) analysis. Results: Serum M2BPGi level correlated with the METAVIR fibrosis score. M2BPGi levels of hepatitis C virus (HCV)-positive patients were significantly higher than those of HCV-negative patients, even in the same fibrosis stage. PHLF ≥ Grade B developed in 19 patients (13.8%). The area under the ROC curve (AUROC) of M2BPGi for the prediction of PHLF ≥ Grade B was 0.71. In multivariate analysis, M2BPGi [odds ratio (OR): 2.08, 95% confidence interval (CI) 1.28–3.55], platelet count (OR: 0.39, 95% CI 0.18–0.80), and resection rate (OR: 2.71, 95% CI 1.46–5.40) were the significant factors associated with PHLF ≥ Grade B. The AUROC of the PHLF index defined by these factors was 0.81. Notably, in patients with HCV infection, the predictive ability of M2BPGi for PHLF (AUROC 0.85) was the best among the preoperative parameters. Conclusions: M2BPGi is a useful predictor of PHLF, especially in patients with HCV infection.

Pancreatic Stellate Cells Have Distinct Characteristics From Hepatic Stellate Cells and Are Not the Unique Origin of Collagen-producing Cells in the Pancreas

Objectives The origin of collagen-producing myofibroblasts in pancreatic fibrosis is still controversial. Pancreatic stellate cells (PSCs), which have been recognized as the pancreatic counterparts of hepatic stellate cells (HSCs), are thought to play an important role in the development of pancreatic fibrosis. However, sources of myofibroblasts other than PSCs may exist because extensive studies of liver fibrosis have uncovered myofibroblasts that did not originate from HSCs. This study aimed to characterize myofibroblasts in an experimental pancreatic fibrosis model in mice. Methods We used transgenic mice expressing green fluorescent protein via the collagen type I &agr;1 promoter and induced pancreatic fibrosis with repetitive injections of cerulein. Results Collagen-producing cells that are negative for glial fibrillary acidic protein (ie, not derived from PSCs) exist in the pancreas. Pancreatic stellate cells had different characteristics from those of HSCs in a very small possession of vitamin A using mass spectrometry and a low expression of lecithin retinol acyltransferase. The microstructure of PSCs was entirely different from that of HSCs using flow cytometry and electron microscopy. Conclusions Our study showed that characteristics of PSCs are different from those of HSCs, and myofibroblasts in the pancreas might be derived not only from PSCs but also from other fibrogenic cells.