Takahiro Dohmen

Eicosapentaenoic acid ameliorates steatohepatitis and hepatocellular carcinoma in hepatocyte-specific Pten-deficient mice☆

BACKGROUND/AIMS Eicosapentaenoic acid (EPA) has been known as a reagent for improving lipid metabolism and inflammation. Hepatocyte-specific Pten-deficient mice exhibit hepatic lesions analogous to non-alcoholic steatohepatitis (NASH). Therefore, we administered EPA to Pten-deficient mice to investigate the mechanisms of NASH. METHODS Pten-deficient mice were assigned to a control group fed with a standard chow or an EPA group fed with a 5% EPA-supplemented standard chow. At 40 weeks, livers from each group were processed to measure triglyceride content, gene expression analysis, Western blotting analysis, and histological examination. Level of serum reactive oxygen species (ROS) was also determined. Forty- and 76-week-old mice were used in tumor burden experiments. RESULTS EPA-ameliorated hepatic steatosis in Pten-deficient mice was based on decreased expression of AMPKalpha1-mediated SREBP-1c and increased PPARalpha expression. The EPA group exhibited less severe chronic hepatic inflammation compared to the control group, resulting from decreased ROS formation and a dramatically low ratio of arachidonic acid to EPA. Moreover, EPA inhibited development of hepatocellular carcinoma (HCC) in Pten-deficient mice based on an inhibition of MAPK activity and a low ratio of oleic to stealic acid, and a reduction in ROS formation. CONCLUSIONS EPA ameliorated steatohepatitis and development of HCC in Pten-deficient mice.

Non‐alcoholic steatohepatitis and hepatocellular carcinoma: Lessons from hepatocyte‐specific phosphatase and tensin homolog (PTEN)‐deficient mice

Non‐alcoholic steatohepatitis (NASH) is a term used to describe a spectrum of conditions characterized by histological findings of hepatic macrovesicular steatosis with inflammation in individuals who consume little or no alcohol. The NASH patients progress to liver cirrhosis and even hepatocellular carcinoma (HCC). Hepatocyte‐specific phosphatase and tensin homolog (PTEN)‐deficient mice (PTEN‐deficient mice), which the authors had generated previously, showed massive hepatomegaly and steatohepatitis with triglyceride accumulation followed by liver fibrosis and HCC, a phenotype similar to human NASH. Therefore, it was shown that PTEN deficiency in hepatocytes could induce hepatic steatosis, inflammation, fibrosis and tumors and that PTEN‐deficient mice were a useful animal model for not only the understanding of the pathogenesis of NASH but also the development of treatment for NASH.

Sex difference in the liver of hepatocyte-specific Pten-deficient mice: A model of nonalcoholic steatohepatitis

Aim:  Nonalcoholic fatty liver disease (NAFLD) is considered to be a public health problem worldwide. NAFLD is more prevalent in men than in women. Tamoxifen, a potent estrogen receptor antagonist, causes nonalcoholic steatohepatitis (NASH), a severe form of NAFLD. Thus, there may be a sex difference that is dependent on estrogens in NAFLD and NASH. Hepatocyte‐specific Pten‐deficient mice exhibit hepatic lesions analogous to NASH and are considered to be a clinical model of NASH. We aimed to shed light on any sex differences in the hepatic lesions of Pten‐deficient mice and the underlying mechanisms.

The roles of interferon regulatory factors 1 and 2 in the progression of human pancreatic cancer.

Objective Pancreatic cancer is one of the most malignant diseases worldwide. Interferon regulatory factor (IRF) 1 and IRF2 function as a tumor suppressor and oncoprotein, respectively, in several types of cancers. We investigated whether IRF1 and IRF2 are involved in the progression of pancreatic cancer. Methods We examined the expressions of IRF1 and IRF2 in pancreatic cancer specimens and analyzed the association with clinicopathologic features. We evaluated the biological effects of IRF1 and IRF2 using a pancreatic cancer cell line. Results The expression levels of IRF1 and IRF2 were decreased and increased, respectively, in the pancreatic cancer cells compared with those observed in the paired normal areas. A higher expression of IRF1 was associated with better features of tumor differentiation, infiltration depth, tumor size, and survival, whereas that of IRF2 was associated with a worse feature of tumor infiltration depth. Interferon regulatory factor 2–overexpressing PANC-1 cells exhibited an increase in cell growth, less apoptotic features, and chemoresistance to gemcitabine treatment. In contrast, IRF1-overexpressing cells exhibited the opposite characteristics. Conclusions Interferon regulatory factors 1 and 2 may regulate the progression of pancreatic cancer by functioning as an antioncoprotein and oncoprotein, respectively. These molecules may serve as potential targets of therapy.

Mao (Ephedra sinica Stapf) protects against D-galactosamine and lipopolysaccharide-induced hepatic failure.

Mao is one component of various traditional herbal medicines. We examined the effects of Mao on an acute liver failure model treated with d-galactosamine (GalN) and lipopolysaccharide (LPS). The lethality of mice administrated Mao with GalN/LPS was significantly decreased compared with that in mice without Mao. Hepatic apoptosis and inflammatory cell infiltration were slight in Mao-treated mice. Serum alanine aminotransferase (ALT) and total bilirubin (T.Bil) activity, tumor necrosis factor alpha (TNF-alpha) levels and caspase 8, 9, and 3 activity in the liver were significantly lower in mice administrated Mao. But, Serum interleukin-6 (IL-6), IL-10 levels and signal transducers and activators of transcription 3 (STAT3) activity in the liver were significantly higher in mice administrated Mao. To investigate the effect of STAT3, we used AG490, which selectively inhibits the activation of Janus kinase (JAK) family tyrosine kinase and inhibits the constitutive activation of STAT3. There was significant aggravation in hepatic apoptosis treated with Mao and AG490 compared with Mao alone. In conclusions, Mao significantly suppressed hepatic apoptosis by inhibition of TNF-alpha production and caspase activity. Furthermore, it is also suggested that Mao, which activates STAT3 induced by IL-6, may be a useful therapeutic tool for fulminant hepatic failure.

Skull metastasis from hepatocellular carcinoma with chronic hepatitis B

A 56-year-old male visited our hospital for evaluation of an occipital mass. Contrast computed tomography showed hypervascular enhancement with osteolytic change in the skull and a huge enhanced mass in the liver. Magnetic resonance imaging showed bone metastasis in the thoracic vertebrae. Assays for hepatitis B surface antigen and hepatitis B core antibody were positive and his liver condition was Child-Pugh grade A. Our diagnosis was hepatocellular carcinoma (HCC) with skull and vertebrae metastases on chronic hepatitis B. He was treated with radiation therapy for bone metastases and transcatheter arterial chemoembolization for HCC. But he developed acute respiratory failure because of aspiration pneumonia, congestion and oedema with haemorrhage of the lungs and died. Dissection showed HCC with multiple bone metastases. The liver tumor was categorized as well-differentiated HCC, Edmondson classification I, trabecular type and pseudoglandular type. In the liver mild infiltration of lymphocytes was seen in Glissons capsules which were significantly enlarged with well preserved limiting plates. Piecemeal necrosis was not obvious. No fibrosis was noted. An 8 cm × 7 cm × 3 cm metastatic lesion had formed in the left occipitotemporal part of the cranial bone. The lesion was osteolytic and showed invasion into the dura mater. Neither the subdural cavity nor the brain showed involvement from the metastatic tumor. However, skull metastasis from HCC is very rare and it affects the patients prognosis and the quality of life. Therefore, it is very important to make an early diagnosis and carry out proper management of skull metastasis from HCC.

Epimorphin protects hepatocytes from oxidative stress by inhibiting mitochondrial injury

Background and Aims:  Many investigations have demonstrated that cell injuries caused by generation of reactive oxygen species (ROS) is a common mechanism of various hepatic disorders. Recently, we have demonstrated that epimorphin, originally cloned as a mesenchymal protein, protects cultured intestinal epithelial cells from ROS. We therefore examine whether epimorphin protects primary cultured hepatocytes from ROS‐induced cell injury.

Efficacy of combined balloon-occluded retrograde transvenous obliteration and simultaneous endoscopic injection sclerotherapy.

OBJECTIVE We evaluated the efficacy and safety of balloon-occluded retrograde transvenous obliteration (B-RTO) performed using absolute ethanol with iodized oil (ET+LPD) and simultaneous endoscopic injection sclerotherapy (EIS) with cyanoacrylate (CA) for gastric varices (GVs). METHODS A total of 16 patients with endoscopically proven high-risk GVs treated using combined B-RTO with ET+LPD and EIS with CA between January 2007 and July 2012 were enrolled. RESULTS Twelve cases included GVs involving both the cardia and fundus, two cases included fundal varices and two cases included cardiac varices. In terms of the form of GVs, 10 cases involved F2 lesions and six cases involved F3 lesions. The flow vein was the left gastric vein in 13 cases and the posterior gastric vein in three cases. The drainage route was a splenorenal shunt in all cases. The average dose of ET+LPD was 12.0 mL, while that of CA was 2.45 mL. All complications were transient, and no major complications occurred after the procedures. None of the patients experienced bleeding or recurrence of gastric varices after the combined B-RTO and EIS procedures during an average follow-up period of 38.3 months. CONCLUSION Combined B-RTO with ET+LPD and simultaneous EIS with CA is considered to be an effective and safe procedure for treating GVs.

Su1476 Efficacy of Combined Balloon-Occluded Retrograde Transvenous Obliteration With Ethanol and Endoscopic Injection Sclerotherapy for Gastric Varices

excluded. Several clinical, biological, ultrasonographic, with Doppler study, and endoscopic data were collected and used to calculate the APRI score (AST to platelets ratio index) and congestion index (CI) of the portal vein (calculated by dividing portal vein cross-sectional area by portal blood velocity). All statistical analysis was performed with SPSS v. 18.0 and a p value of less than 0,05 was considered statistically significant. The performance of the scores was evaluated by the area under the receiver operating characteristic curve (AUROC). Results: 36 patients were included, 64% males, with mean age 60±8,6 years. On On endoscopy, 12 patients (33%) had no EV, 14 patients (39%) had small EV and 10 patients (28%) had large EV. Portal vein diameter was higher in patients with EV than those without EV, while platelet count and portal blood velocity were lower, however with no statistical difference, (p>0,05). APRI score and CI were good predictors for the presence of EV (AUROC 0.74 and 0,635 respectively). The combination of the APRI score for liver fibrosis and CI as a surrogate of portal hypertension resulted in an even more powerful predictor of the presence of EV (AUROC 0,797) and the best cutoff value was 0,075 (sensitivity 79,2%, specificity 75%, positive predictive value 86,4% and negative predictive value 64,3). Conclusions: APRI score and CI of the portal vein are good noninvasive tests to predict esophageal varices. The combination of both models is even more powerful to be used as a method to select cirrhotic patients who need to undergo upper GI endoscopy.

Su1471 Noninvasive Evaluation of the Risk of Hepatocellular Carcinoma Oncogenesis in Chronic Hepatic Disease by Measuring Shear Wave Velocity

Partially Hydrolyzed Guar Gum (PHGG) Attenuates Nonalcoholic Steatohepatitis (NASH) in Mice Through the Gut-Liver Axis Kazuhiro Katada, Yuji Naito, Tomohisa Takagi, Katsura Mizushima, Yasuki Higashimura, Tetsuya Okayama, Naohisa Yoshida, Kazuhiro Kamada, Kazuhiko Uchiyama, Ishikawa Takeshi, Osamu Handa, Hideyuki Konishi, Nobuaki Yagi, Hiroshi Ichikawa, Zenta Yasukawa, Makoto Tokunaga, Tsutomu Okubo, Lekh R. Juneja, Yoshito Itoh