Ei Kataoka

Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas

PTEN is a tumor suppressor gene mutated in many human cancers, and its expression is reduced or absent in almost half of hepatoma patients. We used the Cre-loxP system to generate a hepatocyte-specific null mutation of Pten in mice (AlbCrePten(flox/flox) mice). AlbCrePten(flox/flox) mice showed massive hepatomegaly and steatohepatitis with triglyceride accumulation, a phenotype similar to human nonalcoholic steatohepatitis. Adipocyte-specific genes were induced in mutant hepatocytes, implying adipogenic-like transformation of these cells. Genes involved in lipogenesis and beta-oxidation were also induced, possibly as a result of elevated levels of the transactivating factors PPARgamma and SREBP1c. Importantly, the loss of Pten function in the liver led to tumorigenesis, with 47% of AlbCrePten(flox/flox) livers developing liver cell adenomas by 44 weeks of age. By 74-78 weeks of age, 100% of AlbCrePten(flox/flox) livers showed adenomas and 66% had hepatocellular carcinomas. AlbCrePten(flox/flox) mice also showed insulin hypersensitivity. In vitro, AlbCrePten(flox/flox) hepatocytes were hyperproliferative and showed increased hyperoxidation with abnormal activation of protein kinase B and MAPK. Pten is thus an important regulator of lipogenesis, glucose metabolism, hepatocyte homeostasis, and tumorigenesis in the liver.

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.

Expression of a 72-kDa heat shock protein, and its cytoprotective function, in gastric mucosa in cirrhotic rats

BackgroundPortal hypertensive gastropathy (PHG) is a clinical entity that is observed frequently in patients with liver cirrhosis. In PHG, gastric mucosa is highly susceptible to mucosal injury caused by noxious agents. Many studies, including ours, have reported that a 72-kDa heat shock protein (HSP72) has a crucial cytoprotective function in gastric mucosa. In this study, we investigated the expression and cytoprotective effect of HSP72 on gastric mucosa in portal hypertensive rats.MethodsPHG was produced by bile duct ligation (BDL) or carbon tetrachloride administration in male Sprague-Dawley rats. The expression of HSP72 in the gastric mucosa was evaluated by Western blotting. Induction of gastric mucosal HSP72 by 6-h water-immersion stress was compared between cirrhotic and control rats. Also, mucosal protective abilities against hydrochloric acid (HCl; 0.6 N) following pretreatment with water-immersion stress to induce HSP72 were studied in both groups.ResultsPortal venous pressure was significantly higher in cirrhotic rats compared with control rats (P < 0.05). Baseline expression (before water-immersion stress) of mucosal HSP72 was significantly lower in cirrhotic rats compared with control rats. HCl-induced gastric mucosal lesions were significantly suppressed in control rats compared with cirrhotic rats, especially when HSP72 was preinduced by water-immersion stress.ConclusionsThese findings suggest that HSP72 in the gastric mucosa plays a crucial role with respect to cytoprotection; the induction of HSP72 may provide therapeutic strategies for protection against mucosal injury in PHG.

Zinc L-carnosine protects against mucosal injury in portal hypertensive gastropathy through induction of heat shock protein 72

Background and Aims:  Increased susceptibility to gastric mucosal injury is observed in portal hypertensive gastropathy (PHG). In this study, the effects of zinc L‐carnosine, an anti‐ulcer drug, were evaluated on expression of heat shock protein (hsp) 72 and cytoprotection in gastric mucosa in a rat model of PHG.

Induction of a 72-kDa heat shock protein and protection against lipopolysaccharide-induced liver injury in cirrhotic rats

Background and Aim:  A 70‐kDa heat shock protein (stress‐inducible HSP70, HSP72) has been reported to be a cytoprotectant in a variety of organs. It has been reported that HSP72 protected non‐cirrhotic rats against endotoxemia. However, its cytoprotective effect against endotoxemia in cirrhotic rats has not yet been studied. In this study, we investigated the cytoprotective effect of HSP72 on lipopolysaccharide (LPS)‐induced liver injury in carbon tetrachloride (CCl4)‐induced cirrhotic rats.

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.

Gabexate mesilate, a synthetic protease inhibitor, attenuates carbon tetrachloride-induced liver injury in rats.

BackgroundGabexate mesilate, a synthetic protease inhibitor, is used to treat acute pancreatitis and disseminated intravascular coagulation because it inhibits various serine proteases; however, whether gabexate mesilate prevents acute liver failure has not yet been studied. The aim of the present study was to investigate the effect of gabexate mesilate in carbon tetrachloride (CCl4)-induced liver injury in rats.MethodsAcute hepatic failure was induced by administration of CCl4 intragastrically to male Sprague–Dawley rats. The effects of gabexate mesilate were examined in terms of serum transaminase levels, liver histology, and the prognosis of rats.ResultsGabexate mesilate treatment significantly decreased the elevation of serum transaminase levels and improved liver histology 24 h after the administration of CCl4 (0.2 ml/100 g rat weight). Plasma tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) decreased significantly in the gabexate mesilate-treated rats compared with saline-treated rats. Gabexate mesilate treatment also significantly improved survival rate after a lethal dose of CCl4 (0.5 ml/100 g rat weight) from 0% to 20%.ConclusionsGabexate mesilate treatment attenuated CCl4-induced liver injury via a suppression of proinflammatory cytokine production. In addition, these investigations suggest that gabexate mesilate treatment may provide therapeutic strategies for human acute liver failure.

Distribution and isoforms of epimorphin in carbon tetrachloride-induced acute liver injury in mice.

Background and Aim:  Epimorphin, a morphoregulatory factor essential to organ development, is believed to direct normal morphogenesis in tissue repair. We examined the dynamics and the roles of epimorphin, a cell surface‐associated molecule detected on mesenchymal cells, in hepatic tissue repair from acute liver injury.

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.