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Dive into the research topics where Kazuhiro Kotoh is active.

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Featured researches published by Kazuhiro Kotoh.


Hepatology Research | 2008

Liver X receptor in cooperation with SREBP-1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease

Nobito Higuchi; Masaki Kato; Yuki Shundo; Hirotaka Tajiri; Masatake Tanaka; Naoki Yamashita; Motoyuki Kohjima; Kazuhiro Kotoh; Makoto Nakamuta; Ryoichi Takayanagi; Munechika Enjoji

Aim:  Nonalcoholic fatty liver disease (NAFLD) is one of the most frequent causes of liver dysfunction and its incidence has increased markedly. However, the mechanisms involved in the pathogenesis of NAFLD in humans have not been thoroughly investigated. Sterol regulatory element binding protein (SREBP)‐1c and carbohydrate responsive element binding protein (ChREBP) are transcriptional factors that regulate the expression of lipogenic genes, including acetyl‐CoA carboxylases (ACCs) and fatty acid synthase (FAS). SREBP‐1c and ChREBP are transactivated by liver X receptor (LXR), a nuclear receptor that regulates the metabolism of cholesterol and fatty acids. To understand the mechanisms involved in the pathogenesis of NAFLD, we investigated the transcriptional factors and lipogenic genes activated in the liver with NAFLD.


Journal of Hepatology | 2013

Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma in patients with chronic hepatitis C: A prospective, multicenter study ☆

Eiichi Ogawa; Norihiro Furusyo; Eiji Kajiwara; Kazuhiro Takahashi; Hideyuki Nomura; Toshihiro Maruyama; Yuichi Tanabe; Takeaki Satoh; Makoto Nakamuta; Kazuhiro Kotoh; Koichi Azuma; Kazufumi Dohmen; Shinji Shimoda; Jun Hayashi

BACKGROUND & AIMS The effects of pegylated interferon (PegIFN) α and ribavirin (RBV) treatment of chronic hepatitis C on the incidence of hepatocellular carcinoma (HCC) have not been well established. This study investigated the impact of treatment outcome on the development of HCC by chronic hepatitis C patients treated with PegIFNα2b and RBV. METHODS This large-scale, prospective, multicenter study consisted of 1013 Japanese chronic hepatitis C patients with no history of HCC (non-cirrhosis, n=863 and cirrhosis, n=150). All patients were treated with PegIFNα2b and RBV and the follow-up period started at the end of the antiviral treatment (median observation period of 3.6 years). The cumulative incidence rate of HCC was estimated using the Kaplan-Meier method, according to treatment outcome. RESULTS Forty-seven patients (4.6%) developed HCC during the observation period. In the non-cirrhosis group, the 5-year cumulative incidence rates of HCC for the sustained virological response (SVR) (1.7%) and transient virological response (3.2%) (TVR: defined as relapse or breakthrough) groups were significantly lower than those of the non-virological response (NVR) group (7.6%) (p=0.003 and p=0.03, respectively). A significantly low rate of incidence of HCC by TVR patients in comparison with NVR patients was found for patients aged 60 years and over, but not for those under 60 years of age. In the cirrhosis group, the 5-year cumulative incidence rates of HCC for the SVR (18.9%) and TVR groups (20.8%) were also significantly lower than those of the NVR group (39.4%) (p=0.03 and p=0.04, respectively). CONCLUSIONS SVR and complete viral suppression during treatment with relapse (TVR) were associated with a lower risk of HCC development when compared with NVR.


Transplantation | 2005

Short-term intensive treatment for donors with hepatic steatosis in living-donor liver transplantation.

Makoto Nakamuta; Shusuke Morizono; Yuji Soejima; Tomoharau Yoshizumi; Shinji Aishima; Shin-ichiro Takasugi; Kengo Yoshimitsu; Munechika Enjoji; Kazuhiro Kotoh; Akinobu Taketomi; Hideaki Uchiyama; Mitsuo Shimada; Hajime Nawata; Yoshihiko Maehara

Background. The use of steatotic livers is associated with increased primary nonfunction in liver transplantation. To reduce the risk of liver injury, we applied a short-term combination therapy of diet, exercise and drugs for 11 living-donor liver transplantation (LDLT) candidates with steatosis. Methods. Subjects were treated with a protein-rich (1000 kcal/day) diet, exercise (600 kcal/day), and bezafibrate (400 mg/day) for 2–8 weeks. Results. The treatment significantly improved macrovesicular steatosis (30±4% vs. 12±2% [mean±SEM], P= 0.0028). Body weight and BMI were significantly reduced (73.7±3.2 kg vs. 66.9±2.9 kg, P=0.0033, 26.4±0.7 kg/m2 vs. 24.1±0.8 kg/m2, P=0.0033). The treatment completely normalized liver function tests and lipid metabolism. Seven treated liver grafts (left lobe) were transplanted to the recipients. We compared transplanted graft function and resected liver function of donors using parameters such as peak total bilirubin, prothrombin time at postoperative day 3, and peak alanine aminotransferase between treated liver (n=7) and donor liver without hepatic steotosis (n=37). The transplanted grafts showed good liver functions, and there was no difference between them with respect to functional parameters. The treated donors also showed good liver functions, and no significant differences in functional parameters. Conclusions. The results of this study indicate that our short-term treatment effectively reduced steatosis and contributed to safer LDLT. Our findings also suggest that even severely steatotic livers can be used for LDLT grafting subsequent to our short-term treatment regimen.


Journal of Gastroenterology and Hepatology | 2001

Prevalence of hepatitis B or C virus infections in patients with non-Hodgkin's lymphoma.

Masami Kuniyoshi; Makoto Nakamuta; Hironori Sakai; Munechika Enjoji; Naoko Kinukawa; Kazuhiro Kotoh; Marie Fukutomi; Masaki Yokota; Hidehiro Nishi; Hiroaki Iwamoto; Naokuni Uike; Junji Nishimura; S Inaba; Yoshiaki Maeda; Hajime Nawata; Koichiro Muta

Background: Hepatitis C virus (HCV) and hepatitis B virus (HBV) are not only hepatotropic, but also lymphotropic viruses. Recently, some reports suggested that these viruses may participate in the development of malignant lymphoproliferative disorders.


Liver International | 2005

High glucose stimulates hepatic stellate cells to proliferate and to produce collagen through free radical production and activation of mitogen-activated protein kinase.

Rie Sugimoto; Munechika Enjoji; Motoyuki Kohjima; Satoshi Tsuruta; Masataka Iwao; Toshiyo Sonta; Kazuhiro Kotoh; Toyoshi Inoguchi; Makoto Nakamuta

Abstract: Background: Nonalcoholic steatohepatitis is a clinicopathologic condition that may progress to liver fibrosis. Hyperglycemia is supposed to be one of the factors inducing hepatic fibrogenesis, but the mechanism has not been fully clarified. Oxidative stress is increasingly found in patients with diabetes/hyperglycemia in which conditions reactive oxygen species (ROS) are produced.


Journal of Hepatology | 2013

Telaprevir can be successfully and safely used to treat older patients with genotype 1b chronic hepatitis C

Norihiro Furusyo; Eiichi Ogawa; Makoto Nakamuta; Eiji Kajiwara; Hideyuki Nomura; Kazufumi Dohmen; Kazuhiro Takahashi; Takeaki Satoh; Koichi Azuma; Akira Kawano; Yuichi Tanabe; Kazuhiro Kotoh; Shinji Shimoda; Jun Hayashi

BACKGROUND & AIMS This study was performed to evaluate the efficacy of a triple therapy in older Japanese patients; telaprevir (TVR) was added to pegylated interferon α2b and ribavirin. METHODS This prospective study enrolled 120 genotype 1b patients with chronic hepatitis C who received 12 weeks of triple therapy followed by a 12-week dual therapy that included pegylated interferon α2b and ribavirin. Patients were categorized according to age: group A, 64 patients aged >60 and group B, 56 patients aged ⩽60. Serum HCV RNA levels were monitored by COBAS TaqMan HCV test. RESULTS The rates of undetectable HCV RNA at week 4 (rapid virological response, RVR) were 73.4% in group A and 73.2% in group B. No significant difference in sustained virological response (SVR) was found between groups A (76.6%) and B (83.9%) (p=0.314). The SVR rates for patients with interleukin 28B (IL28B) (rs8099917) TT allele (89.4% and 91.9% for groups A and B) were significantly higher than for those with the IL28B TG/GG allele (41.2% and 68.4%, respectively) (both p<0.05). Multivariate analysis extracted IL28B TT and RVR as independent factors associated with SVR. Adverse effects resulted in treatment discontinuation by 12.5% in each group. Hemoglobin decrease significantly differed between groups A and B: the decrease to ≤100 g/L, to 85 - <100g/L, and to <85 g/L, was 9.4%, 40.6%, and 50% in group A patients, respectively, and 41.1%, 25%, and 33.9% in group B patients, respectively (p=0.0006). CONCLUSIONS TVR-based triple therapy can be successfully used to treat older patients with genotype 1b chronic hepatitis C.


Lipids in Health and Disease | 2010

NPC1L1 inhibitor ezetimibe is a reliable therapeutic agent for non-obese patients with nonalcoholic fatty liver disease

Munechika Enjoji; Kazuyuki Machida; Motoyuki Kohjima; Masaki Kato; Kazuhiro Kotoh; Kazuhisa Matsunaga; Manabu Nakashima; Makoto Nakamuta

BackgroundWe recently examined the distribution of abdominal fat, dietary intake and biochemical data in patients with nonalcoholic fatty liver disease (NAFLD) and found that non-obese NAFLD patients did not necessarily exhibit insulin resistance and/or dysregulated secretion of adipocytokines. However, dietary cholesterol intake was superabundant in non-obese patients compared with obese patients, although total energy and carbohydrate intake was not excessive. Therefore, excess cholesterol intake appears to be one of the main factors associated with NAFLD development and liver injury.MethodsWe reviewed a year of follow-up data of non-obese NAFLD patients treated with Niemann-Pick C1 like 1 inhibitor ezetimibe to evaluate its therapeutic effect on clinical parameters related to NAFLD. Without any dietary or exercise modification, 10 mg/day of ezetimibe was given to 8 patients. In 4 of 8 patients, ezetimibe was administered initially. In the remaining 4 patients, medication was switched from ursodeoxycholic acid to ezetimibe.ResultsIn each patient, body mass index was maintained under 25 kg/m2 during the observation period. Serum ALT levels significantly decreased within 6 months and in 4 patients levels reached the normal range (<30 U/L), which was accompanied with at least a 10% decrease in serum total cholesterol and LDL-cholesterol. However, ultrasonographic findings of fatty liver did not show obvious improvement for a year.ConclusionWe conclude that the cholesterol absorption inhibitor ezetimibe can suppress hepatic injury in non-obese patients with NAFLD and that ezetimibe may offer a novel treatment for NAFLD.


Molecular Medicine Reports | 2011

Increased hepatic expression of dipeptidyl peptidase-4 in non-alcoholic fatty liver disease and its association with insulin resistance and glucose metabolism

Masayuki Miyazaki; Masaki Kato; Kosuke Tanaka; Masatake Tanaka; Motoyuki Kohjima; Kazuhiko Nakamura; Munechika Enjoji; Makoto Nakamuta; Kazuhiro Kotoh; Ryoichi Takayanagi

Dipeptidyl peptidase-4 (DPP4) is a serine protease that degrades glucagon-like peptide-1 (GLP-1), an incretin hormone that stimulates insulin secretion from pancreatic β-cells. DPP4 is also involved in the regulation of T cell-mediated inflammatory processes. These properties of DPP4 suggest that it may play a role in the progression of non-alcoholic fatty liver disease (NAFLD). Hepatic DPP4 mRNA expression levels were analyzed by real-time PCR using liver biopsy samples from 17 NAFLD patients and 10 healthy subjects. In NAFLD patients, we also examined correlations between DPP4 expression levels and metabolic factors, including homeostasis model assessment-insulin resistance (HOMA-IR), body mass index (BMI), and serum cholesterol and triglyceride levels. To examine the potential effects of nutritional factors, DPP4 expression levels were analyzed in HepG2 cells subjected to various culture conditions. Hepatic DPP4 mRNA expression was significantly greater in NAFLD patients than in control subjects. DPP4 expression levels were negatively correlated with HOMA-IR and positively correlated with serum cholesterol levels. In HepG2 cells, high glucose significantly enhanced DPP4 expression, whereas insulin, fatty acids and cholesterol did not. Increased hepatic expression of DPP4 in NAFLD may be associated with metabolic factors, including insulin resistance, and may adversely affect glucose metabolism in this liver disease.


Liver International | 2005

Effect of IL-4 and IL-13 on collagen production in cultured LI90 human hepatic stellate cells

Rie Sugimoto; Munechika Enjoji; Makoto Nakamuta; Satoshi Ohta; Motoyuki Kohjima; Masami Kuniyoshi; Eiichiro Arimura; Shusuke Morizono; Kazuhiro Kotoh; Hajime Nawata

Background: Recently, it has been reported that interleukin 4 (IL‐4) and 13 (IL‐13) directly activate fibroblasts and promote fibrosis. In the process of hepatic fibrosis, the effects of these cytokines on hepatic stellate cells (HSCs) are not well known.


Journal of Cellular Biochemistry | 2011

Potential role of branched‐chain amino acids in glucose metabolism through the accelerated induction of the glucose‐sensing apparatus in the liver

Nobito Higuchi; Masaki Kato; Masayuki Miyazaki; Masatake Tanaka; Motoyuki Kohjima; Tetsuhide Ito; Makoto Nakamuta; Munechika Enjoji; Kazuhiro Kotoh; Ryoichi Takayanagi

Branched‐chain amino acids (BCAAs) have a potential to improve glucose metabolism in cirrhotic patients; however, the contribution of liver in this process has not been clarified. To estimate the effect of BCAA on glucose metabolism in liver, we evaluated the mRNA expression levels of glucose‐sensing apparatus genes in HepG2 cells and in rat liver after oral administration of BCAA. HepG2 cells were cultured in low glucose (100 mg/dl) or high glucose (400 mg/dl) in the absence or presence of BCAA. The mRNA expression levels and protein levels of GLUT2 and liver‐type glucokinase (L‐GK) were estimated using RT‐PCR and immunoblotting. The expression levels of transcriptional factors, including SREBP‐1c, ChREBP, PPAR‐γm and LXRα, were estimated. The mRNA expression levels of transcriptional factors, glycogen synthase, and genes involved in gluconeogenesis were evaluated in rat liver at 3 h after the administration of BCAA. BCAA accelerated the expression of GLUT2 and L‐GK in HepG2 cells in high glucose. Expression levels of ChREBP, SREBP‐1c, and LXRα were also increased in this condition. BCAA administration enhanced the mRNA expression levels of L‐GK, SREBP‐1c, and LXRα and suppressed the expression levels of G‐6‐Pase in rat liver, without affecting the expression levels of glycogen synthase or serum glucose concentrations. BCAA administration enhanced the bioactivity of the glucose‐sensing apparatus, probably via the activation of a transcriptional mechanism, suggesting that these amino acids may improve glucose metabolism through the accelerated utility of glucose and glucose‐6‐phosphate in the liver. J. Cell. Biochem. 112: 30–38, 2011.

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Eiji Kajiwara

Memorial Hospital of South Bend

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