Atsushi Umemura

High expression of p300 in HCC predicts shortened overall survival in association with enhanced epithelial mesenchymal transition of HCC cells

P300 impacts the transcription of several genes involved in biological behavior of human malignancies including hepatocellular carcinomas (HCC). We found p300 is highly expressed in 47% of surgically resected HCC specimens by immunohistochemistry, which correlated with advanced TNM staging (P = 0.034), vascular invasion (P = 0.036), intrahepatic metastasis (P = 0.001) and shortened overall survival (P = 0.028). In vitro study, knocking down of p300 expression in hepatoma cells recovered E-cadherin expression, inhibited the translocation of beta (β)-catenin into the nuclei, decreased cyclin D1 activity and suppressed the migration/invasion of HCC cells. Furthermore, suppression of p300 led to down-regulation of epithelial-mesenchymal transition (EMT)-related molecules such as Snail, Twist and HIF-1 alpha. These observations suggest that p300 contributes to the EMT-related progression of HCCs.

Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-Fed db/db mice

Our previous study revealed that blockade of interleukin-6 (IL-6)–STAT3 signaling ameliorated liver injury, although hepatic STAT3−/− or GP130−/− mice have been reported to develop severe liver injury, in a murine methionine choline deficient (MCD) diet-induced model of non-alcoholic steatohepatitis (NASH). In this study, to determine whether profound blockade of IL-6–STAT3 signaling may still ameliorate liver injury, we studied db/db mice, which have impaired leptin-mediated STAT3 activation, using the MCD diet-induced NASH model. Male lean and db/db mice (6 weeks old) were fed either control chow or an MCD diet for 8 or 12 weeks. Half of the mice were treated with 15u2009mg/kg rat anti-mouse IL-6 receptor neutralizing antibody (MR16-1) intraperitoneally twice weekly, the remainder were injected with 15u2009mg/kg rat IgG as a control. Hepatic steatosis, injury, fibrosis, markers of lipid peroxidation/oxidant stress and antiapoptotic gene expression were evaluated. Plasma IL-6 levels were elevated in all groups of db/db mice. Although hepatic IL-6/ GP130 signaling was activated in chow-fed db/db mice, this was suppressed in MCD diet-fed db/db mice, accompanied by downregulation of hepatic IL-6 receptor and GP130 mRNA expression. MR16-1 treatment of MCD diet-fed db/db mice further repressed STAT3 activities and expression of STAT3-related antiapoptotic genes, such as Bcl-2 and Ref-1, but increased plasma-free fatty acid and hepatic markers of lipid peroxidation/oxidant stress, leading to increased liver injury, hepatocyte apoptosis and liver fibrosis. Although ‘moderate’ blockade of enhanced IL-6–STAT3 signaling may be beneficial in NASH, as we reported previously, these findings demonstrate that a profound defect in STAT3 activation is detrimental in terms of liver injury, hepatocyte apoptosis and liver fibrosis, indicating the hepato-protective role of IL-6 signaling in this severe NASH model.

Blockade of interleukin 6 signalling ameliorates systemic insulin resistance through upregulation of glucose uptake in skeletal muscle and improves hepatic steatosis in high‐fat diet fed mice

Mice fed high‐fat diet (HFD) demonstrate obesity‐related systemic insulin resistance (IR). Aim of this study is to clarify the role of interleukin (IL)‐6 in IR in vivo focusing on skeletal muscle, adipose tissue and liver.

Genome-wide DNA methylation analysis in hepatocellular carcinoma

Epigenetic changes as well as genetic changes are mechanisms of tumorigenesis. We aimed to identify novel genes that are silenced by DNA hypermethylation in hepatocellular carcinoma (HCC). We screened for genes with promoter DNA hypermethylation using a genome-wide methylation microarray analysis in primary HCC (the discovery set). The microarray analysis revealed that there were 2,670 CpG sites that significantly differed in regards to the methylation level between the tumor and non-tumor liver tissues; 875 were significantly hypermethylated and 1,795 were significantly hypomethylated in the HCC tumors compared to the non‑tumor tissues. Further analyses using methylation-specific PCR, combined with expression analysis, in the validation set of primary HCC showed that, in addition to three known tumor-suppressor genes (APC, CDKN2A, and GSTP1), eight genes (AKR1B1, GRASP, MAP9, NXPE3, RSPH9, SPINT2, STEAP4, and ZNF154) were significantly hypermethylated and downregulated in the HCC tumors compared to the non-tumor liver tissues. Our results suggest that epigenetic silencing of these genes may be associated with HCC.

Current status and future prospects of chemotherapy for advanced hepatocellular carcinoma

Sorafenib is the only drug that demonstrates a survival benefit for advanced hepatocellular carcinoma (HCC). However, the therapeutic effect of sorafenib is limited, so development of a more effective treatment method and second-line treatments is needed. Since the advent of sorafenib, clinical studies have been conducted with a variety of drugs and treatment methods, mainly with molecular targeted therapy, but almost all trials have ended in failure. The reasons for the difficulty in the development of a novel drug or treatment method include the diversity of mechanisms in the carcinogenesis and development of HCC, as well as the presence of background liver diseases such as chronic hepatitis and cirrhosis. Trials with immune-checkpoint inhibitors, which have an entirely different anti-tumor mechanism from that of molecular targeted drugs or cytotoxic drugs, have recently begun. Based on the results to date, clinical trials are now being conducted with enriched target subjects. In the future, providing more individualized treatment approaches for patients with advanced HCC will be essential.

Effect of sodium glucose cotransporter 2 inhibitor on liver function tests in Japanese patients with non-alcoholic fatty liver disease and type 2 diabetes mellitus.

No pharmacological therapies have been established for non‐alcoholic fatty liver disease (NAFLD). Sodium glucose cotransporter 2 inhibitor (SGLT2I) was developed for the treatment of adults with type 2 diabetes mellitus (T2DM). The aim of this retrospective study is to evaluate the efficacy of SGLT2I in NAFLD patients with T2DM.Aims nNo pharmacological therapies have been established for nonalcoholic fatty liver disease (NAFLD). Sodium glucose co-transporter 2 inhibitor (SGLT2I) developed for the treatment of adults with type 2 diabetes (T2DM). The aim of this retrospective study is to evaluate the efficacy of SGLT2I in NAFLD patients with T2DM n nMethods nTwenty-four biopsy-proven NAFLD patients with T2DM who received SGLT2I for 24u2009weeks were retrospectively enrolled as the SGLT2I group. Another 21 NAFLD patients with T2DM treated with dipeptidyl peptidase-4 inhibiter (DPP4I, sitagliptin) for 24u2009weeks were selected as the DPP4I group. Clinical data were evaluated at baseline and at 4, 12, 24u2009weeks. Seventeen patients in SGLT2I group were evaluated body composition (Inbody 720) before and after therapy. n nResults nNot only body weight and HbA1c but also transaminase activities were significantly decreased in the SGLT2I group. Reductions in transaminase activities were similar between SGLT2I and DPP4I groups. In the SGLT2I group, body mass indexu3000and fasting plasma glucose also decreased after the treatment. n nConclusion nSGLT2I can be a novel promising agent for the treatment for NAFLD patients with T2DM. Prospective randomized controlled trial are warranted to confirm this efficacy of SGLT2I on NAFLD with T2DM.

Development of hepatocellular carcinoma in Japanese patients with biopsy-proven non-alcoholic fatty liver disease: Association between PNPLA3 genotype and hepatocarcinogenesis/fibrosis progression

Some patients with non‐alcoholic fatty liver disease (NAFLD) develop hepatocellular carcinoma (HCC). Patatin‐like phospholipase domain containing 3 (PNPLA3) rs738409 (encoding the I148M variant) has been associated with advanced fibrosis and HCC. We determined the risk factors for HCC, including the PNPLA3 rs738409 polymorphism, in Japanese patients with biopsy‐proven NAFLD.

Effect of sodium-glucose cotransporter 2 inhibitor on liver function tests in NAFLD patients with type 2 diabetes in Japan

No pharmacological therapies have been established for non‐alcoholic fatty liver disease (NAFLD). Sodium glucose cotransporter 2 inhibitor (SGLT2I) was developed for the treatment of adults with type 2 diabetes mellitus (T2DM). The aim of this retrospective study is to evaluate the efficacy of SGLT2I in NAFLD patients with T2DM.Aims nNo pharmacological therapies have been established for nonalcoholic fatty liver disease (NAFLD). Sodium glucose co-transporter 2 inhibitor (SGLT2I) developed for the treatment of adults with type 2 diabetes (T2DM). The aim of this retrospective study is to evaluate the efficacy of SGLT2I in NAFLD patients with T2DM n nMethods nTwenty-four biopsy-proven NAFLD patients with T2DM who received SGLT2I for 24u2009weeks were retrospectively enrolled as the SGLT2I group. Another 21 NAFLD patients with T2DM treated with dipeptidyl peptidase-4 inhibiter (DPP4I, sitagliptin) for 24u2009weeks were selected as the DPP4I group. Clinical data were evaluated at baseline and at 4, 12, 24u2009weeks. Seventeen patients in SGLT2I group were evaluated body composition (Inbody 720) before and after therapy. n nResults nNot only body weight and HbA1c but also transaminase activities were significantly decreased in the SGLT2I group. Reductions in transaminase activities were similar between SGLT2I and DPP4I groups. In the SGLT2I group, body mass indexu3000and fasting plasma glucose also decreased after the treatment. n nConclusion nSGLT2I can be a novel promising agent for the treatment for NAFLD patients with T2DM. Prospective randomized controlled trial are warranted to confirm this efficacy of SGLT2I on NAFLD with T2DM.

Insulin resistance increases the risk of incident type 2 diabetes mellitus in patients with nonalcoholic fatty liver disease

Type 2 diabetes mellitus (T2DM) is a major complication of patients with non‐alcoholic fatty liver disease (NAFLD). The aim of this retrospective study is to determine the risk factors for development of T2DM in patients with biopsy‐proven NAFLD.

Effect of 12-week dulaglutide therapy in Japanese patients with biopsy-proven non-alcoholic fatty liver disease and type 2 diabetes mellitus.

Aims nNo pharmacological therapies have been established for nonalcoholic fatty liver disease (NAFLD) with type 2 diabetes mellitus (T2DM). The aim of this retrospective study is to evaluate the efficacy and safety of dulaglutide, a novel glucagon-like peptidase-1 receptor (GLP-1R) agonist in Japanese NAFLD patients with T2DM. n nMethods nFifteen biopsy-proven NAFLD patients with T2DM refractory to diet intervention who received once weekly dulaglutide 0.75u2009mg for 12u2009weeks were retrospectively enrolled after exclusion of two patients dropped off by 12u2009weeks. In five patients, transient elastography and body composition (Inbody 720) were also evaluated before and after the treatment. n nResults nNot only body weight and HbA1c but also transaminase activities were significantly decreased after the 12wk therapy with dulaglutide. Total body fat mass and liver stiffness measurement also decreased after the treatment. n nConclusion nDulaglutide, a new GLP-1R agonist, can be a novel promising agent for the treatment for NAFLD patients with T2DM due to its efficacy of body weight reductions, the nature of weekly injection and patient preference. Prospective randomized controlled trials are warranted to confirm this impact of dulaglutide on NAFLD with T2DM.No pharmacological therapies have been established for non‐alcoholic fatty liver disease (NAFLD) with type 2 diabetes mellitus (T2DM). The aim of this retrospective study is to evaluate the efficacy and safety of dulaglutide, a novel glucagon‐like peptidase‐1 receptor agonist, in Japanese NAFLD patients with T2DM.