代謝関連核内受容体遺伝子変異機能解析と肥満および脂質代謝異常

代谢相关核受体基因突变与肥胖和脂质代谢异常的功能分析

• 批准号: 17790603
• 负责人: 野原 淳
• 金额: $ 2.18万
• 依托单位: Kanazawa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17790603/
• 关键词: 核内受容体; 家族性複合型高脂血症; 遺伝子多型; リポ蛋白リパーゼ; 冠動脈硬化症; 肥満; メタボリックシンドローム; 遺伝子変異; 脂肪肝; コレステロール代謝

核内受容体は特有のリガンド存在下に多数の遺伝子群を協調的に発現制御する転写因子で,フィブラート剤チアゾリジン剤は,それぞれ核内受容体PPARαおよびγを標的としている.PPARsに限らずRetinoid-X-receptor (RXR)とヘテロダイマーを形成して作用する核内受容体は,近年代謝に重要な多数の遺伝子の制御が示され,MetSに代表される代謝疾患治療戦略の重要な標的となっている.しかし,動物実験では明らかでもヒトでも同じとは限らない.この点で機能的遺伝子変異の同定は重要な知見を与えるものであり,また核内受容体を標的とする治療の開発には必須の情報でもある.我々は高脂血症患者を対象としてPPARα,γ,δ,LXRα,Farnesoid-X-receptor (FXR),RXRγ遺伝子を検索,これまでに4個のミスセンス型(PPARαG395E, PPARαD140N, PPARγ2 P12A, RXRγG14S)と5'端非翻訳領域の多型1個(FXR -1g->t)を同定した.RXRγ S14多型保持者は一般人(5%)と比較しFCHLに有意に高頻度(15%)で,TG高値およびHDL-C低値であり,冠動脈造影施行105例でcoronary stenosis indexが有意に高値であった.機能解析でRXRγS14は機能亢進型であり,リポ蛋白リパーゼプロモーター配列の転写をより強く抑制した.これらの結果よりRXRγ遺伝子はFCHLの遺伝子背景に何らかの寄与をしていると考えられた.FXR遺伝子-1g->t多型では-1t保持者は有意にBMI高値,TC低値,拡張期血圧低値,腹部USで脂肪肝は低頻度と多彩な影響がみられた.またスタチンを投与した症例の解析では,FXR-1t保持者は-1gg保持者に比べより強くTchが低下,治療効果の予測にも重要と考えられた.

Nuclear receptors are unique regulatory factors that coordinate the development of multiple genetic subgroups in the presence of unique ligands, and they can be used as targets for nuclear receptors PPARα and γ.PPARs limit the formation and function of the Retinoid-X-receptor (RXR) and receptor receptors, and in recent years have been shown to control most of the genes that are important in metabolism. MetS represents an important target in the treatment of metabolic disorders. The animal is the same as the animal. The function of the gene is different and the same is important. The information is necessary for the development of the nuclear receptor. In this study, we investigated the effects of PPARα,γ,δ,LXRα,Farnesoid-X-receptor (FXR),RXRγ on hyperlipidemia patients.(PPARαG395E, PPARαD140N, PPARγ2 P12A, RXRγG14S) 1 polymorphism in 5'non-inverted domain (FXR -1g->t) Same as fixed.RXRγ S14 polytype maintainer average (5%) Comparison FCHL intentionally high frequency (15%) TG high value <$HDL-C low value <$, coronary angiography performed 105 cases <$coronary stensis index <$intentionally high value <$. Function analysis RXRγS14 is hyperfunctional, and its protein distribution is strongly inhibited. FXR γ gene is the most frequent gene in FCHL gene background.FXR γ gene-1g->t polymorphism is the most frequent gene in FCHL gene background. FXR-1t Keeper-1gg Keeper-1gg Keeper-1

项目成果

Effects of fenofibrate therapy on plasma ubiquinol-10 and ubiquinone-10 levels in Japanese patients with hyperlipidemia and type 2 diabetes mellitus.

非诺贝特治疗对日本高脂血症和 2 型糖尿病患者血浆泛醇 10 和泛醌 10 水平的影响。

• 发表时间: 2006
• 期刊: Pharmacotherapy. 26(4)
• 作者: Viana AY;Sakoda H;et al.;Kushiyama A et al.;Yoko Warabi;Yoko Warabi;蕨 陽子;蕨 陽子;Haneda E et al.;Yoshiyama Y et al.;Fujiwara H et al.;Huang SM et al.;He M et al.;Higuchi M et al.;Araya R et al.;Higuchi M et al.;Higuchi M et al.;Higuchi M et al.;Saito T et al.;Atsushi Nohara;Junji Kobayashi;Junji Kobayashi;Junji Kobayashi;Mutsuko Takata;Akimichi Asano
• 通讯作者: Akimichi Asano

ATP-binding cassette transporter G8 M429V polymorphism as a novel genetic marker of higher cholesterol absorption in hypercholesterolaemic Japanese subjects

• DOI: 10.1042/cs20050030
• 发表时间: 2005-08-01
• 期刊: CLINICAL SCIENCE
• 影响因子: 6
• 作者: Miwa, K;Inazu, A;Mabuchi, H
• 通讯作者: Mabuchi, H

CETP (cholesteryl ester transfer protein) promoter -1337 C>T polymorphism protects against coronary atherosclerosis in Japanese patients with heterozygous familial hypercholesterolaemia.

CETP（胆固醇酯转移蛋白）启动子-1337 C>T 多态性可预防日本杂合子家族性高胆固醇血症患者的冠状动脉粥样硬化。

• 发表时间: 2006
• 期刊: Clin Sci 111(5)
• 作者: Viana AY;Sakoda H;et al.;Kushiyama A et al.;Yoko Warabi;Yoko Warabi;蕨 陽子;蕨 陽子;Haneda E et al.;Yoshiyama Y et al.;Fujiwara H et al.;Huang SM et al.;He M et al.;Higuchi M et al.;Araya R et al.;Higuchi M et al.;Higuchi M et al.;Higuchi M et al.;Saito T et al.;Atsushi Nohara;Junji Kobayashi;Junji Kobayashi;Junji Kobayashi;Mutsuko Takata
• 通讯作者: Mutsuko Takata

Long-term course of lipoprotein lipase (LPL) deficiency due to homozygous LPL(Arita) in a patient with recurrent pancreatitis, retained glucose tolerance, and atherosclerosis

患有复发性胰腺炎、保留糖耐量和动脉粥样硬化的患者因纯合 LPL(Arita) 导致脂​​蛋白脂肪酶 (LPL) 缺乏的长期病程

• 发表时间: 2005
• 期刊: J Clin Endocrinol Metab 90(12)
• 作者: Viana AY;Sakoda H;et al.;Kushiyama A et al.;Yoko Warabi;Yoko Warabi;蕨 陽子;蕨 陽子;Haneda E et al.;Yoshiyama Y et al.;Fujiwara H et al.;Huang SM et al.;He M et al.;Higuchi M et al.;Araya R et al.;Higuchi M et al.;Higuchi M et al.;Higuchi M et al.;Saito T et al.;Atsushi Nohara;Junji Kobayashi;Junji Kobayashi;Junji Kobayashi;Mutsuko Takata;Akimichi Asano;Nohara A;Miwa K;Kawashiri M
• 通讯作者: Kawashiri M

RXRg Gene Variant is Associate with Lower HDL, Lower Lipoprotein Lipase, Advanced Coronary Artery Disease, and More Frequent in Familial Combined Hyperlipidemia

RXRg 基因变异与低 HDL、低脂蛋白脂肪酶、晚期冠状动脉疾病以及家族性混合性高脂血症相关

• 发表时间: 2005
• 期刊: Circulation (Supplement) 112(17)
• 作者: Viana AY;Sakoda H;et al.;Kushiyama A et al.;Yoko Warabi;Yoko Warabi;蕨 陽子;蕨 陽子;Haneda E et al.;Yoshiyama Y et al.;Fujiwara H et al.;Huang SM et al.;He M et al.;Higuchi M et al.;Araya R et al.;Higuchi M et al.;Higuchi M et al.;Higuchi M et al.;Saito T et al.;Atsushi Nohara;Junji Kobayashi;Junji Kobayashi;Junji Kobayashi;Mutsuko Takata;Akimichi Asano;Nohara A
• 通讯作者: Nohara A