Molecular mechanism underlying the regulation of lipid metabolism via lipid transportsome and its failure

脂质转运体调控脂质代谢的分子机制及其失败

• 批准号: 23659142
• 负责人: AKAHANE Satomi
• 金额: $ 2.41万
• 依托单位: Toho University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23659142/
• 关键词: 脂質代謝; 胆汁酸; コレステロール; トリグリセリド; 肝臓; 脂質転移蛋白; マウス; リポ蛋白

STARD10, a member of the steroidogenic acute regulatory protein (StAR)-related lipid transfer (START) protein family, is highly expressed in the liver and has been shown to transfer phosphatidylcholine. Therefore it has been assumed that STARD10 may function in the secretion of phospholipids into the bile. To help elucidate the physiological role of STARD10, we produced Stard10knockout mice (Stard10^-/-) and studied their phenotype.Neither liver content nor biliary secretion of phosphatidylcholine was altered in Stard10^-/-mice. Unexpectedly, the biliary secretion of bile acids from the liver and the level of taurine-conjugated bile acids in bile were significantly higher in Stard10^-/-mice than wild type (WT) mice.In contrast, the levels of the secondary bile acids were lower in the liver of Stard10-/-mice, suggesting that the enterohepatic cycling is impaired.STARD10 was also expressed in the gallbladder and small intestine where the expression level of apical sodium dependent bile acid transporter (ASBT) turned out to be markedly lower in Stard10^-/-mice than in WT mice when measured under fed condition.Consistent with the above results, the fecal excretion of bile acids was significantly increased in Stard10^-/-mice. Interestingly, PPARa-dependent genes responsible for the regulation of bile acid metabolism were down-regulated in the liver of Stard10^-/-mice.The loss of STARD10 impaired the PPARa activity and the expression of a PPARa-target gene such as Cyp8b1in mouse hepatoma cells. These results indicate that STARD10 is involved in regulating bile acid metabolism through the modulation of PPARa-mediated mechanism.

STARD 10是类固醇生成急性调节蛋白（星星）相关脂质转移（START）蛋白家族的成员，在肝脏中高度表达，并已显示可转移磷脂酰胆碱。因此，已经假定STARD 10可能在磷脂分泌到胆汁中中起作用。为了帮助阐明STARD 10的生理作用，我们制造了Stard 10基因敲除小鼠（Stard 10 ^-/-）并研究了它们的表型。Stard 10 ^-/-小鼠的肝脏含量和胆汁分泌的磷脂酰胆碱均未发生改变。出乎意料的是，Stard 10 ^-/-小鼠从肝脏胆汁分泌的胆汁酸和胆汁中牛磺酸结合胆汁酸的水平显著高于野生型（WT）小鼠。相反，Stard 10 ^-/-小鼠肝脏中次级胆汁酸的水平较低，STARD 10在胆囊和小肠中也有表达，其中顶端钠依赖性胆汁的表达水平与小肠中的表达水平相一致。在进食状态下测定时，发现Stard 10 ^-/-小鼠的胆汁酸转运蛋白（ASBT）显著低于WT小鼠，与上述结果一致，Stard 10 ^-/-小鼠的粪便胆汁酸排泄显著增加。有趣的是，在Stard 10 ^-/-小鼠的肝脏中，负责调节胆汁酸代谢的PPARa依赖性基因表达下调，STARD 10的缺失损害了小鼠肝癌细胞中PPARa的活性和PPARa靶基因如Cyp 8b 1的表达。这些结果表明STARD 10通过调节PPARa介导的机制参与调节胆汁酸代谢。

项目成果

脂質転移タンパク質STARD10の胆汁酸調節における役割

脂质转运蛋白 STARD10 在胆汁酸调节中的作用

• 发表时间: 2011
• 作者: 伊藤雅方;山梨義英;高田龍平;中瀬古(泉)寛子;杉山篤;鈴木洋史;赤羽悟美
• 通讯作者: 赤羽悟美

L型Ca^<2+>チャネルのポア入り口付近のアミノ酸がCa^<2+>選択性に重要である

L型Ca^2+通道孔入口附近的氨基酸对于Ca^2+选择性很重要

• 发表时间: 2011
• 作者: 中瀬古(泉)寛子;杉山篤;赤羽悟美
• 通讯作者: 赤羽悟美

房結節緩徐脱分極に関与するCa^2+チャネル分子種の薬理学的検討:efonidipine光学異性体、nifedipineの活動電位波形およびCav1.2、Cav1.3、Cav3.1チャネルに対する作用

参与心房结缓慢去极化的Ca^2+通道分子种类的药理学研究：动作电位波形以及依福地平光学异构体和硝苯地平对Cav1.2、Cav1.3和Cav3.1通道的影响

• 发表时间: 2011
• 作者: 行方衣由紀;恒岡弥生;小川 亨;古美門千紗;高原 章;中瀬古寛子;赤羽悟美;田中光
• 通讯作者: 田中光

Comparison of the effects of levofloxacin on QT/QTc interval assessed in both healthy Japanese and Caucasian subjects.

比较左氧氟沙星对健康日本人和白种人受试者的 QT/QTc 间期的影响。

• 发表时间: 2012
• 期刊: Br J Clin Pharmacol
• 作者: Kitahara K;Nakamura Y;Tsuneoka Y;Adachi-Akahane S;Tanaka H;Yamazaki H;Takahara A;Yamazaki J;Ikeda T;Sugiyama A;Sugiyama A
• 通讯作者: Sugiyama A

Cardiohemodynamic and Electrophysiological Effects of Anti-influenza Drug Oseltamivir In Vivo and In Vitro

• DOI: 10.1007/s12012-013-9202-6
• 发表时间: 2013-09-01
• 期刊: CARDIOVASCULAR TOXICOLOGY
• 影响因子: 3.2
• 作者: Kitahara, Ken;Nakamura, Yuji;Sugiyama, Atsushi
• 通讯作者: Sugiyama, Atsushi