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| 1.
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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
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
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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.
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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
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
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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.
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Xu, Liang ; Nagata, Naoto ; Ota, Tsuguhito ; 長田, 直人 ; 太田, 嗣人
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金沢大学医薬保健研究域医学系<br />Obesity is a low-grade sustained inflammatory state that causes oxidative stress in different metabo
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lic tissues, which leads to insulin resistance and nonalcoholic fatty liver disease (NAFLD). Particularly, obesity-induced metabolic endotoxemia plays an important role in the pathogenesis of insulin resistance and inflammation. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of antioxidant signaling that serves as a primary cellular defense against the cytotoxic effects of oxidative stress. Pharmacological stimulation of Nrf2 mitigates obesity and insulin resistance in mice; however, Nrf2 activators are not clinically available due to biosafety concerns. A recent study demonstrated that glucoraphanin, a precursor of the Nrf2 activator sulforaphane, ameliorates obesity by enhancing energy expenditure and browning of white adipose tissue, and attenuates obesity-related inflammation and insulin resistance by polarizing M2 macrophages and reducing metabolic endotoxemia. Thus, this review focuses on the efficiency and safety of glucoraphanin in alleviating obesity, insulin resistance, and NAFLD.<br />Embargo Period 12 months
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Fuke, Nobuo ; Nagata, Naoto ; Suganuma, Hiroyuki ; Ota, Tsuguhito ; 長田, 直人 ; 太田, 嗣人
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金沢大学医学系細胞分子機能学<br />Metabolic endotoxemia is a condition in which blood lipopolysaccharide (LPS) levels are elevated, re
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gardless of the presence of obvious infection. It has been suggested to lead to chronic inflammation-related diseases such as obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease (NAFLD), pancreatitis, amyotrophic lateral sclerosis, and Alzheimer's disease. In addition, it has attracted attention as a target for the prevention and treatment of these chronic diseases. As metabolic endotoxemia was first reported in mice that were fed a high-fat diet, research regarding its relationship with diets has been actively conducted in humans and animals. In this review, we summarize the relationship between fat intake and induction of metabolic endotoxemia, focusing on gut dysbiosis and the influx, kinetics, and metabolism of LPS. We also summarize the recent findings about dietary factors that attenuate metabolic endotoxemia, focusing on the regulation of gut microbiota. We hope that in the future, control of metabolic endotoxemia using dietary factors will help maintain human health.
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伊藤, さつき ; 石崎, 純子 ; 小柴, 美紀恵 ; 五十嵐, 康郎 ; 長田, 直人 ; 菅, 幸生 ; 西村, 良成 ; 前馬, 秀明 ; 小泉, 晶一 ; 中尾, 眞二 ; 横川, 弘一 ; 崔, 吉道 ; 宮本, 謙一
概要:
The purpose of this study was to investigate whether the trough plasma concentration of voriconazole (VRCZ) in the stead
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y-state (Cmin) influences efficacy and safety in adult and pediatric patients. Treatment was successful in 75% of pediatric patients and 56% of adult patients,and there was no association between Cmin and efficacy.However,liver dysfunction occurred more frequently in the case that Cmin was over 4μg/mL in both adult and pediatric patients.Also,pediatric patients,especially those younger than 2 years,required a higher dose of VRCZ than adults to achieve a similar Cmin. We concluded that the use of VRCZ at a constant dose over a long period may lead to an increase in Cmin.Therefore,careful,continuous monitoring of the Cmin of VRCZ is necessary for pediatric patients,particularly recipients of hematopoietic stem cell transplantation.
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長田, 直人 ; Nagata, Naoto
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金沢大学医薬保健研究域医学系<br />ブロッコリースプラウトに含まれる機能性因子グルコラファニンを混ぜた高脂肪食を与えたマウスは体重増加率が約15％抑えられ，内臓脂肪量が約20％減少し，脂肪肝と血糖値の上昇が抑えられた。その作用機序として
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，グルコラファニンが，①脱共役タンパク質１（UCP-1）を増加させ，エネルギー消費の増加と脂肪燃焼をもたらすBrowningを促進した。また，②グルコラファニンは，内毒素（LPS）を過剰産生するデスルフォビブリオ科の腸内細菌の増殖を抑制しており，血液中の内毒素を低下させ，代謝性エンドトキシン血症を改善するという作用を発見した。さらに，グルコラファニンの標的分子として転写因子Nrf2が重要であった。<br />Glucoraphanin, a phytochemical in broccoli sprouts, attenuated weight gain, decreased hepatic steatosis, and improved glucose tolerance and insulin sensitivity in high fat diet (HFD)-fed wild-type mice but not in HFD-fed Nrf2 knockout mice. Glucoraphanin increased uncoupling protein-1 (Ucp-1) protein levels in subcutaneous adipose depots, thereby increased energy expenditure. In addition, glucoraphanin suppressed Desulfovibrionaceae in gut microbiomes of HFD-fed mice, and decreased plasma lipopolysaccharide levels. By promoting fat browning, limiting metabolicendotoxemia-related chronic inflammation, and modulatingredox stress, glucoraphanin may mitigate obesity, insulin resistance, and nonalcoholic fatty liver disease.<br />研究課題/領域番号:15K00813, 研究期間(年度):2015-04-01 - 2018-03-31
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長田, 直人 ; Nagata, Naoto
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金沢大学医薬保健研究域医学系<br />近年、高脂肪食や運動習慣の欠如を背景として、脂肪肝炎（NASH）が急増している。本研究の目的は、過栄養状態の肝臓において発現が亢進するSrc homology phosphatase 2 (Shp2)
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が肝臓の脂肪蓄積と炎症の誘導・維持をいかに制御しているかを明らかにすることである。本研究によって、１）肝臓特異的Shp2欠損マウスは、特殊飼料による肝臓への脂肪蓄積と炎症を著明に抑制した。２）Shp2阻害剤の投与は特殊飼料による脂肪肝炎を部分的にではあるが改善することが明らかとなった。従って、Shp2が脂肪肝炎の新しい治療標的分子となりうる所見が得られたと考える。<br />Recently, non-alcoholic steatohepatitis has been rapidly increasing due to a high-fat diet and/or lack of exercise. Aim of this study is to investigate the role of Src homology phosphatase 2 (Shp2) in regulation of lipid metabolism and inflammation in the liver of mice model of NASH.This study revealed that liver-specific deficiency of Shp2 reduced lipid accumulation and inflammation in the liver of mice fed CDAA diet. I also found that Shp2 inhibitor partially improved CDAA diet-induced NASH. Taken together, Shp2 might be a novel molecular target of NASH.<br />研究課題/領域番号:25860526, 研究期間(年度):2013-04-01 - 2015-03-31
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長田, 直人 ; Nagata, Naoto
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高コレステロール食によって作成した脂肪肝炎モデルマウスに対して,酪酸菌製剤の投与した.投与後、4、8、16、および32週のいずれの時点においても肝臓では脂肪蓄積、炎症、および線維化のいずれもが抑制されていた。今回の研究において,酪酸がAMP
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activated protein kinase(AMPK)を活性化させること、および酪酸がヒストンのアセチル化を促進させることにより脂肪酸β酸化系遺伝子の発現を上昇させることを培養細胞を用いて新たに見出した。酪酸菌製剤は、高コレステロール食によって誘導される脂肪肝炎を改善する可能性がある。<br />We tested to treat atherogenic-diet (high cholesterol diet) induced steatohepatitis in mice by Clostridium Butyricum. After 4, 8, 16, and 32 weeks treatment, the atherogenic diet-induced steatosis, inflammation, and fibrosis were improved in the mice liver. We demonstrated that butyrate up-regulates fatty acid beta oxidation via activation AMP activated protein kinase and histone acetylation in vitro. Clostridium Butyricum may improve non-alcoholic steatohepatitis.
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