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Kobayashi, Mio ; Kakuda, Yuko ; Harada, Kenichi ; Sato, Yasunori ; Sasaki, Motoko ; Ikeda, Hiroko ; Terada, Mitsuhiro ; Mukai, Munenori ; Kaneko, Shuichi ; Nakanuma, Yasuni ; 小林, 水緒 ; 原田, 憲一 ; 佐藤, 保則 ; 佐々木, 素子 ; 池田, 博子 ; 金子, 周一 ; 中沼, 安二
出版情報: World Journal of Gastroenterology.  20  pp.3597-3608,  2014.  Baishideng Publishing Group Co
URL: http://hdl.handle.net/2297/00061729
概要: 金沢大学医薬保健研究域医学系<br />AIM: To investigate histological and immunohistochemical differences in hepatitis between autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC) with AIH features. METHODS: Liver needle biopsies of 41 PBC with AIH features and 43 AIH patients were examined. The activity of periportal and lobular inflammation was scored 0 (none or minimal activity) to 4 (severe), and the degree of hepatitic rosette formation and emperipolesis was semiquantatively scored 0-3. The infiltration of mononuclear cells positive for CD20, CD38, CD3, CD4, and CD8 and positive for immunoglobulins (IgG, IgM, and IgA) at the periportal areas (interface hepatitis) and in the hepatic lobules (lobular hepatitis) were semiquantitatively scored in immunostained liver sections (score 0-6). Serum aspartate aminotransferase (AST), immunoglobulins, and autoantibodies at the time of liver biopsy were correlated with the histological and immunohistochemical scores of individual lesions. RESULTS: Lobular hepatitis, hepatitic rosette formation, and emperipolesis were more extensive and frequent in AIH than in PBC. CD3+, CD4+, and CD8+ cell infiltration scores were higher in the hepatic lobules and at the interface in AIH but were also found in PBC. The degree of mononuclear cell infiltration correlated well with the degree of interface and lobular hepatitis in PBC, but to a lesser degree in AIH. CD20+ cells were mainly found in the portal tracts and, occasionally, at the interface in both diseases. Elevated AST correlated well with the hepatocyte necroinflammation and mononuclear cell infiltration, specifically CD38+ cells in PBC. No correlation existed between autoantibodies and inflammatory cell infiltration in PBC or AIH. While most AIH cases were IgG-predominant at the interface, PBC cases were divided into IgM-predominant, IgM/IgGequal, and IgG-predominant types, with the latter sharing several features with AIH. CONCLUSION: These results suggest that the hepatocellular injuries associated with interface and lobular hepatitis in AIH and PBC with interface hepatitis may not be identical. © 2014 Baishideng Publishing Group Co., Limited. All rights reserved. 続きを見る
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Xu, Liang ; Nagata, Naoto ; Nagashimada, Mayumi ; Zhuge, Fen ; Ni, Yinhua ; Chen, Guanliang ; Mayoux, Eric ; Kaneko, Shuichi ; Ota, Tsuguhito ; 長田, 直人 ; 金子, 周一 ; 太田, 嗣人
出版情報: EBioMedicine.  20  pp.137-149,  2017-07.  Elsevier
URL: http://hdl.handle.net/2297/00050482
概要: 金沢大学医薬保健研究域医学系<br />Sodium-glucose cotransporter (SGLT) 2 inhibitors increase urinary glucose excretion (UGE), leading t o blood glucose reductions and weight loss. However, the impacts of SGLT2 inhibition on energy homeostasis and obesity-induced insulin resistance are less well known. Here, we show that empagliflozin, a SGLT2 inhibitor, enhanced energy expenditure and attenuated inflammation and insulin resistance in high-fat-diet-induced obese (DIO) mice. C57BL/6J mice were pair-fed a high-fat diet (HFD) or a HFD with empagliflozin for 16 weeks. Empagliflozin administration increased UGE in the DIO mice, whereas it suppressed HFD-induced weight gain, insulin resistance, and hepatic steatosis. Moreover, empagliflozin shifted energy metabolism towards fat utilization, elevated AMP-activated protein kinase and acetyl-CoA carbolxylase phosphorylation in skeletal muscle, and increased hepatic and plasma fibroblast growth factor 21 levels. Importantly, empagliflozin increased energy expenditure, heat production, and the expression of uncoupling protein 1 in brown fat and in inguinal and epididymal white adipose tissue (WAT). Furthermore, empagliflozin reduced M1-polarized macrophage accumulation while inducing the anti-inflammatory M2 phenotype of macrophages within WAT and liver, lowering plasma TNFα levels and attenuating obesity-related chronic inflammation. Thus, empagliflozin suppressed weight gain by enhancing fat utilization and browning and attenuated obesity-induced inflammation and insulin resistance by polarizing M2 macrophages in WAT and liver. 続きを見る
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Xu, Liang ; Nagata, Naoto ; Nagashimada, Mayumi ; Zhuge, Fen ; Ni, Yinhua ; Chen, Guanliang ; Kamei, Junzo ; Ishikawa, Hiroki ; Komatsu, Yasuhiko ; Kaneko, Shuichi ; Ota, Tsuguhito ; 長田, 直人 ; 金子, 周一 ; 太田, 嗣人
出版情報: Oncotarget.  9  pp.15047-15060,  2018.  Impact Journals LLC
URL: http://hdl.handle.net/2297/00050483
概要: 金沢大学医薬保健研究域医学系<br />Nonalcoholic fatty liver disease (NAFLD) is caused by ectopic fat accumulation in the liver. NAFLD i s associated with hepatic inflammation and oxidative stress, resulting in nonalcoholic steatohepatitis (NASH) with advanced fibrosis. Placental extracts have been used to treat various chronic diseases due to their antioxidative effect. However, the effects of the extracts on the development of NASH have yet to be elucidated. Here, we demonstrated that supplementation with an oral porcine placental extract (PPE) attenuated lipid accumulation and peroxidation, insulin resistance, inflammatory and stress signaling, and fibrogenesis in the liver of NASH model mice fed a high-cholesterol and high-fat diet. The PPE reduced the number of M1-like liver macrophages, but increased the number of anti-inflammatory M2-like macrophages, resulting in a predominance of M2 over M1 macrophage populations in the liver of NASH mice. Accordingly, the PPE suppressed lipopolysaccharide-induced M1 polarization in isolated murine peritoneal macrophages, whereas it facilitated interleukin 4-induced M2 polarization. Furthermore, the PPE reduced the hepatic stellate cell (HSC) activation associated with the attenuated transforming growth factor-β/Smad3 signaling, both in the liver of NASH mice and in RI-T cells, a HSC line. The PPE may be a potential approach to prevent NASH by limiting lipid peroxidation, promoting M2 macrophage polarization, and attenuating HSC activation. © Xu et al. 続きを見る
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Nasti, Alessandro ; Sakai, Yoshio ; Seki, Akihiro ; Buffa, Geraldine Belen ; Komura, Takuya ; Mochida, Hatsune ; Yamato, Masatoshi ; Yoshida, Keiko ; Ho, Tuyen T. B. ; Takamura, Masayuki ; Usui, Soichiro ; Wada, Takashi ; Honda, Masao ; Kaneko, Shuichi ; 酒井, 佳夫 ; 餅田, 初音 ; 吉田, 佳子 ; 高村, 雅之 ; 薄井, 荘一郎 ; 和田, 隆志 ; 本多, 政夫 ; 金子, 周一
出版情報: European Journal of Immunology.  47  pp.2163-2174,  2017-12.  Wiley
URL: http://hdl.handle.net/2297/00050487
概要: 金沢大学医薬保健研究域医学系<br />Stromal cells in adipose tissue are useful for repair/regenerative therapy as they harbor a substant ial number of mesenchymal stem cells; therefore, freshly isolated autologous uncultured adipose tissue derived stromal cells (u-ADSCs) are useful for regenerative therapy, and obviate the need for mesenchymal stem cells. We evaluated the therapeutic effect of murine u-ADSCs and sorted subsets of u-ADSCs in a concanavalin A (ConA) induced murine model of hepatitis, as well as their characteristics. We found that 10–20% of u-ADSCs expressed the CD45 leukocyte-related antigen. CD68, which is a marker of macrophages (MΦs), was expressed by 50% of CD45+ u-ADSCs. About 90% of CD68+CD45+ cells expressed CD206 antigen, which is a marker of inhibitory M2-type MΦs. Genes related to M2-type MUs were especially more highly expressed by CD45+CD206+ u-ADSCs than by CD45− u-ADSCs. CD45+ u-ADSCs inhibited the expression of cytokines/chemokines and suppressed the proliferation of splenocytes stimulated with ConA. We observed that not only whole u-ADSCs, but also the CD45+ subset of u-ADSCs ameliorated the ConA-induced hepatitis in mice. In conclusion, we show that freshly isolated murine u-ADSCs were effective against acute hepatitis, and CD45+ u-ADSCs acting phenotypically and functionally like M2-type MΦs, contributed to the repair of liver tissue undergoing inflammation. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim<br />Embargo Period 12 months 続きを見る
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Hayashi, Tomoyuki ; Yamashita, Taro ; Terashima, Takeshi ; Suda, Tsuyoshi ; Okada, Hikari ; Asahina, Yoshiro ; Hayashi, Takehiro ; Hara, Yasumasa ; Nio, Kouki ; Sunagozaka, Hajime ; Takatori, Hajime ; Arai, Kuniaki ; Yamashita, Tatsuya ; Mizukoshi, Eishiro ; Honda, Masao ; Kaneko, Shuichi ; 林, 智之 ; 山下, 太郎 ; 寺島, 健志 ; 須田, 烈史 ; 岡田, 光 ; 朝日向, 良朗 ; 丹尾, 幸樹 ; 砂子阪, 肇 ; 鷹取, 元 ; 荒井, 邦明 ; 山下, 竜也 ; 水腰, 英四郎 ; 本多, 政夫 ; 金子, 周一
出版情報: BMC Cancer.  17  pp.870-,  2017-12-19.  BioMed Central Ltd.
URL: http://hdl.handle.net/2297/00050515
概要: 金沢大学先進予防医学研究科<br />Background: Sorafenib is a multiple receptor tyrosine kinase inhibitor known to prolong overall survi val in patients with advanced hepatocellular carcinoma (HCC). Predicting this drug's survival benefits is challenging because clinical responses are rarely measurable during treatment. In this study, we hypothesized that serum cytokines levels could predict the survival of advanced HCC patients, as sorafenib targets signaling pathways activated in the tumor stromal microenvironment and potentially affects serum cytokine profiles. Methods: Of 143 patients with advanced-stage HCC, 104 who were recruited between 2003 and 2007 received hepatic arterial infusion chemotherapy (HAIC) that mainly targets tumor epithelial cells at S-phase (cohort 1); additionally, 39 recruited between 2010 and 2012 received sorafenib, which primarily targets the stromal vascular endothelial cells. Serum samples were collected and aliquoted prior to the treatment. Serum EGF, bFGF, HGF, IFN-γ, IL-10, IL-12, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10, MIG, PDGF-BB, SCF, SDF1, TGF-β, TGF-α, TNF-α, and VEGF-A were measured via enzyme-linked immunosorbent assays. The Modified Response Evaluation Criteria in Solid Tumors were used to assess tumor responses. Results: The median survival time of HCC patients in cohorts 1 (HAIC-treated) and 2 (sorafenib-treated) were 12.0 and 12.4 months, respectively. Kaplan-Meier analysis revealed no significant survival differences between the 2 groups. Patients who survived more than 2 years after sorafenib treatment exhibited higher serum levels of IL-10, IL-12, TNF-a, IL-8, SDF-1, EGF, PDGF-BB, SCF, and TGF-α. Furthermore, cohort 2 patients with higher serum IL-5 (>12 pg/mL), IL-8 (>10 pg/mL), PDGF-BB (>300 pg/mL), and VEGF-A (>50 pg/mL) levels achieved longer survival; cohort 1 patients did not. Hierarchical cluster analysis of 6 cytokines robustly enriched for comparison analysis between cohorts 1 and 2 (IL-5, IL-8, TGF-α, PDGF-BB, CXCL9, and VEGF-A) revealed that elevation of these cytokines correlated with better survival when treated with sorafenib but not with HAIC. Conclusions: Patients who exhibited survival benefits owing to sorafenib treatment tended to present higher serum cytokines levels, potentially reflecting the activation of stromal signaling in the tumor microenvironment. Our study thus introduces novel biomarkers that may identify advanced HCC patients who may experience survival benefits with sorafenib treatment. © 2017 The Author(s). 続きを見る
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Hara, Akinori ; Furuichi, Kengo ; Koshino, Akihiko ; Yasuda, Haruka ; Tran, Trang Thi Thu ; Iwata, Yasunori ; Sakai, Norihiko ; Shimizu, Miho ; Kaneko, Shuichi ; Nakamura, Hiroyuki ; Wada, Takashi ; 原, 章規 ; 古市, 賢吾 ; 岩田, 恭宜 ; 坂井, 宣彦 ; 清水, 美保 ; 金子, 周一 ; 中村, 裕之 ; 和田, 隆志
出版情報: Kidney International Reports.  3  pp.133-141,  2018-01-01.  Elsevier Inc
URL: http://hdl.handle.net/2297/00050598
概要: 金沢大学医薬保健研究域医学系<br />Introduction: We examined the impact of autoantibodies on the erythropoietin receptor (EPOR) in type 2 diabetic patients with chronic kidney disease (CKD). Methods: A total of 112 Japanese patients with type 2 diabetes who had CKD were enrolled in this study and followed for a mean of 45 months. Sera from these patients were screened for anti-EPOR antibodies using enzyme-linked immunosorbent assays. Results: Anti-EPOR antibodies were detected in 26 patients (23%). Anti-EPOR antibodies were associated with low hemoglobin concentrations and decreased renal function. In patients with biopsy-proven diabetic nephropathy, anti-EPOR antibodies were associated with increased levels of interstitial inflammation. A decrease in renal function was observed more frequently in patients with antibodies than in those without antibodies, and the presence of the antibodies together with well-known clinical parameters, including proteinuria and low glomerular filtration rate, was a significant risk factor for end-stage renal disease. In human tubular epithelial HK-2 cells, IgG fractions containing anti-EPOR antibodies upregulated the expression of monocyte chemoattractant protein-1 mRNA under a high concentration of glucose. Conclusion: Anti-EPOR antibodies might be involved in the progression of renal lesions and in the impaired erythropoiesis in type 2 diabetic patients with CKD. Furthermore, the presence of anti-EPOR antibodies may be an additional predictor for end-stage renal disease in type 2 diabetes. © 2017 International Society of Nephrology<br />Embargo Period 12 months 続きを見る
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石田, 晃介 ; 島上, 哲朗 ; 金子, 周一 ; Ishida, Kosuke ; Shimakami, Tetsuro ; Kaneko, Shuichi
出版情報: 日本老年医学会雑誌 = Japanese Journal of Geriatrics.  54  pp.375-380,  2017.  日本老年医学会 = The Japan Geriatrics Society
URL: http://hdl.handle.net/2297/00054183
概要: Aim: Antiviral treatment for hepatitis C infection in elderly patients has been dramatically improved by direct-acting a ntivirals (DAAs). DAAs are easy to use as they are administered orally and the treatment periods are shorter. Furthermore, they are associated with fewer adverse effects. In this study, we sought to analyze the efficacy and safety of DAAs in HCV-infected elderly patients.Method: We analyzed 223 HCV-infected patients who were treated with DAAs in Kanazawa University Hospital, Japan. As of August 31, 2016, all of the patients were observed to have achieved a sustained viral response by the 12th week of treatment (SVR12). We categorized patients into two groups. Group one included 79 patients (average age 75.5 years; range 70-85 years). Group two included 144 patients (average age, 58.1 years; range 27-69 years). Group one included more female patients.Results: The platelet count of Group one was significantly lower than that of Group two. The FIB-4 index of Group one was significantly higher than that of Group two. Group one included a greater number of patients with a history of hepatocellular carcinoma (HCC) before the administration of DAAs. The SVR12 rate and rate of drop-out due to adverse effects did not differ between the two groups to a statistically significant extent. The rate of HCC occurrence after SVR in Group one was higher than that in Group two.Conclusion: Our study shows that DAAs can be used for older patients and that the antiviral efficacy and safety are similar to the efficacy and safety in younger patients.<br />目的:C型慢性肝疾患に対する抗ウイルス療法は,直接作用型抗ウイルス薬(以下DAA)の登場で高率にウイルス駆除が可能となった.今回,当院においてDAAによる抗ウイルス療法を施行したC型慢性肝疾患症例を対象として,高齢者に対するDAAの有効性,安全性を検討した.方法:金沢大学附属病院においてDAAを導入したC型慢性肝疾患症例のうち,2016年8月までに治療終了後12週間目の持続的ウイルス学的著効(Sustained Viral Response at week 12 after treatment is completed:SVR12)の判定が可能であった223例を対象とした.治療開始時の年齢が70歳以上を高齢群,70歳未満を若年群として両群の臨床背景,抗ウイルス効果,有害事象を解析した.結果:全223例中,高齢群は79例,若年群は144例であった.年齢は高齢群で75.5±4.4歳,若年群で58.1±9.8歳(平均±SD),最年長は85歳,最年少は27歳であった.性別は高齢群で有意に女性が多かった(p<0.01).血小板数は高齢群で13.7±6.4×104/μl,若年群で15.9±7.0×104/μl と有意に高齢群で低値であり(p=0.02),FIB-4 Indexも高齢群で5.12±3.25,若年群で3.48±2.89と有意に高齢群が高値であった(p<0.01).肝癌既往歴を有する症例は,高齢群で79例中39例,若年群で144例中29例であり,高齢群で有意に多かった(p<0.01).血清AFP値は高齢群で12.5±20.3 ng/ml,若年群で15.7±22.3 ng/mlと有意差は認めなかった.DAA導入前の前治療は高齢群で79例中49例,若年群で144例中63例に治療歴があり,高齢群で有意に前治療歴を有する症例が多かった(p=0.01).治療効果は高齢群が79例中71例(89.9%),若年群が144例中131例(91.0%)でSVR12を達成しており,有意差は認めなかった.副作用中止は高齢群で79例中4例(5.1%),若年群で144例中4例(2.8%)に認めたが,有意差は認めなかった.SVR12達成後の肝発癌は高齢群で79例中17例,若年群で144例中12例に認め,有意に高齢群で多かった(p<0.01).結論:DAAの治療効果,副作用は両群間に差を認めず,高齢者においても安全に治療可能であった.しかし,高齢群では肝線維化進展例,肝癌治療歴を有する症例が多く,ウイルス駆除後の発癌に留意すべきである.<br />出版者の許可を得て登録 続きを見る
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Iwata, Yasunori ; Wada, Takashi ; Yokoyama, Hitoshi ; Toyama, Tadashi ; Kitajima, Shinji ; Okumura, Toshiya ; Hara, Akinori ; Yamahana, Junya ; Nakaya, Izaya ; Kobayashi, Motoo ; Kitagawa, Kiyoki ; Kokubo, Satoshi ; Yoshimoto, Keiichi ; Shimizu, Kazuaki ; Sakai, Norihiko ; Furuichi, Kengo ; Koshino, Yoshitaka ; Takaeda, Chikako ; Takeda, Shinichi ; Takasawa, Kazuya ; Ohta, Satoshi ; Takaeda, Masayoshi ; Kaneko, Shuichi
出版情報: Internal Medicine.  46  pp.447-452,  2007-04-08.  日本内科学会
URL: http://hdl.handle.net/2297/6249
概要: 金沢大学保健管理センター<br />金沢大学大学院医学系研究科<br />金沢大学附属病院<br />Background: In hemodialysis patients, adynamic bone disease has been reported to be closely associated with low levels of parathyroid hormone (PTH) due to exposure to high levels of serum calcium following the administration of calcium carbonate (CaCO3) or vitamin D agents. This study was conducted to clarify the therapeutic effect of a non-calcemic phosphate binder, sevelamer hydrochloride (sevelamer), for hypoparathyroidism in hemodialysis patients with or without diabetes mellitus. Methods: Based on entry criteria, 40 Japanese chronic hemodialysis patients (22 males and 18 females with a mean age of 60.6, 14 diabetic patients and 26 non-diabetic patients) were switched from CaCO3 to sevelamer for 48 weeks. Serum calcium, phosphate, intact (i) PTH and PTH-(1-84) were analyzed. Bone remodeling activity was evaluated by determining intact osteocalcine (iOC), bone-specific alkaline phosphatase (BAP). Results: The switch from CaCO3 to sevelamer significantly decreased the serum levels of calcium, resulting in the elevation of iPTH levels from 31±18 pg/mL to 95±96 pg/mL by 48 weeks. In contrast, serum phosphate levels remained similar to those in patients with CaCO3 treatment. Concomitantly, the levels of BAP and iOC were elevated. Further, these beneficial effects on bone turnover were observed in both diabetic and non-diabetic patients. Conclusion: Sevelamer reduced the calcium concentration and thereby increased PTH levels, resulting in the improvement of markers of bone turnover. The administration of sevelamer is of therapeutic benefit for the improvement of bone remodeling activity even in hemodialysis patients with diabetes. © 2007 The Japanese Society of Internal Medicine. 続きを見る
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Misu, Hirofumi ; Takamura, Toshinari ; Takayama, Hiroaki ; Hayashi, Hiroto ; Matsuzawa-Nagata, Naoto ; Kurita, Seiichiro ; Ishikura, Kazuhide ; Ando, Hitoshi ; Takeshita, Yumie ; Ota, Tsuguhito ; Sakurai, Masaru ; Yamashita, Tatsuya ; Mizukoshi, Eishiro ; Yamashita, Taro ; Honda, Masao ; Miyamoto, Kenichi ; Kubota, Tetsuya ; Kubota, Naoto ; Kadowaki, Takashi ; Kim, Han-Jong ; Lee, In-kyu ; Minokoshi, Yasuhiko ; Saito, Yoshiro ; Takahashi, Kazuhiko ; Yamada, Yoshihiro ; Takakura, Nobuyuki ; Kaneko, Shuichi
出版情報: Cell Metabolism.  12  pp.483-495,  2010-11-03.  Elsevier
URL: http://hdl.handle.net/2297/25782
概要: 金沢大学医薬保健研究域医学系<br />The liver may regulate glucose homeostasis by modulating the sensitivity/resistance of peripheral ti ssues to insulin, by way of the production of secretory proteins, termed hepatokines. Here, we demonstrate that selenoprotein P (SeP), a liver-derived secretory protein, causes insulin resistance. Using serial analysis of gene expression (SAGE) and DNA chip methods, we found that hepatic SeP mRNA levels correlated with insulin resistance in humans. Administration of purified SeP impaired insulin signaling and dysregulated glucose metabolism in both hepatocytes and myocytes. Conversely, both genetic deletion and RNA interference-mediated knockdown of SeP improved systemic insulin sensitivity and glucose tolerance in mice. The metabolic actions of SeP were mediated, at least partly, by inactivation of adenosine monophosphate-activated protein kinase (AMPK). In summary, these results demonstrate a role of SeP in the regulation of glucose metabolism and insulin sensitivity and suggest that SeP may be a therapeutic target for type 2 diabetes. © 2010 Elsevier Inc. 続きを見る
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Nakamura, Seiji ; Takamura, Toshinari ; Matsuzawa-Nagata, Naoto ; Takayama, Hiroaki ; Misu, Hirofumi ; Noda, Hiroyo ; Nabemoto, Satoko ; Kurita, Seiichiro ; Ota, Tsuguhito ; Ando, Hitoshi ; Miyamoto, Kenichi ; Kaneko, Shuichi
出版情報: The Journal of biological chemistry.  284  pp.14809-14818,  2009-05-29.  American Society for Biochemistry and Molecular Biology
URL: http://hdl.handle.net/2297/18986
概要: Visceral adiposity in obesity causes excessive free fatty acid (FFA) flux into the liver via the portal vein and may cau se fatty liver disease and hepatic insulin resistance. However, because animal models of insulin resistance induced by lipid infusion or a high fat diet are complex and may be accompanied by alterations not restricted to the liver, it is difficult to determine the contribution of FFAs to hepatic insulin resistance. Therefore, we treated H4IIEC3 cells, a rat hepatocyte cell line, with a monounsaturated fatty acid (oleate) and a saturated fatty acid (palmitate) to investigate the direct and initial effects of FFAs on hepatocytes. We show that palmitate, but not oleate, inhibited insulin-stimulated tyrosine phosphorylation of insulin receptor substrate 2 and serine phosphorylation of Akt, through c-Jun NH2-terminal kinase (JNK) activation. Among the well established stimuli for JNK activation, reactive oxygen species (ROS) played a causal role in palmitate-induced JNK activation. In addition, etomoxir, an inhibitor of carnitine palmitoyltransferase-1, which is the rate-limiting enzyme in mitochondrial fatty acid β-oxidation, as well as inhibitors of the mitochondrial respiratory chain complex (thenoyltrifluoroacetone and carbonyl cyanide m-chlorophenylhydrazone) decreased palmitate-induced ROS production. Together, our findings in hepatocytes indicate that palmitate inhibited insulin signal transduction through JNK activation and that accelerated β-oxidation of palmitate caused excess electron flux in the mitochondrial respiratory chain, resulting in increased ROS generation. Thus, mitochondria-derived ROS induced by palmitate may be major contributors to JNK activation and cellular insulin resistance. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc. 続きを見る