Ito Masanori, Yamanashi Yoshihide, Toyoda Yu, Izumi-Nakaseko Hiroko, Oda Satoko, Sugiyama Atsushi, Kuroda Masaru, Suzuki Hiroshi, Takada Tappei, Adachi-Akahane Satomi
Department of Pharmacology, School of Medicine, Faculty of Medicine, Toho University, Ota-ku, Tokyo, Japan.
Biochim Biophys Acta. 2013 Feb;1831(2):459-68. doi: 10.1016/j.bbalip.2012.11.008. Epub 2012 Nov 28.
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 Stard10 knockout 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 the 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, PPARα-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 PPARα activity and the expression of a PPARα-target gene such as Cyp8b1 in mouse hepatoma cells. These results indicate that STARD10 is involved in regulating bile acid metabolism through the modulation of PPARα-mediated mechanism.
类固醇生成急性调节蛋白（StAR）相关脂质转运（START）蛋白家族成员STARD10在肝脏中高表达，且已证实其可转运磷脂酰胆碱。因此，人们推测STARD10可能在磷脂分泌到胆汁的过程中发挥作用。为了帮助阐明STARD10的生理作用，我们制备了Stard10基因敲除小鼠（Stard10(-/-)）并研究其表型。在Stard10(-/-)小鼠中，磷脂酰胆碱的肝脏含量和胆汁分泌均未改变。出乎意料的是，Stard10(-/-)小鼠肝脏中胆汁酸的胆汁分泌以及胆汁中牛磺酸结合型胆汁酸的水平显著高于野生型（WT）小鼠。相反，Stard10(-/-)小鼠肝脏中次级胆汁酸的水平较低，这表明肠肝循环受损。STARD10在胆囊和小肠中也有表达，在喂食条件下测量时，Stard10(-/-)小鼠顶端钠依赖性胆汁酸转运体（ASBT）的表达水平明显低于WT小鼠。与上述结果一致，Stard10(-/-)小鼠胆汁酸的粪便排泄显著增加。有趣的是，负责调节胆汁酸代谢的PPARα依赖性基因在Stard10(-/-)小鼠肝脏中下调。在小鼠肝癌细胞中，STARD10缺失会损害PPARα活性以及PPARα靶基因（如Cyp8b1）的表达。这些结果表明，STARD10通过调节PPARα介导的机制参与胆汁酸代谢的调节。
