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

STARD10是甾体性急性调节蛋白（StAR）相关脂质转移（START）蛋白家族的一员，在肝脏中高表达，并已被证明可转移磷脂酰胆碱。因此，有推测认为STARD10可能在磷脂分泌到胆汁中起作用。为了帮助阐明STARD10的生理作用，我们培育了STARD10基因敲除小鼠（STARD10 ^-/-）并研究了它们的表型。在Stard10^-/-小鼠中，肝脏磷脂酰胆碱含量和胆汁分泌均未发生改变。出乎意料的是，与野生型（WT）小鼠相比，Stard10^-/-小鼠的肝脏胆汁酸分泌量和胆汁中牛磺酸共轭胆汁酸水平显著升高。相比之下，Stard10-/-小鼠肝脏中二级胆汁酸水平较低，表明肠肝循环受损。在喂养条件下，STARD10 ^-/-小鼠的胆囊和小肠中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^-/-小鼠的粪便胆汁酸排泄量显著增加。有趣的是，负责调节胆汁酸代谢的ppara依赖基因在Stard10^-/-小鼠的肝脏中下调。STARD10的缺失损害了小鼠肝癌细胞中PPARa活性和PPARa靶基因cyp8b1的表达。这些结果表明，STARD10通过ppara介导的机制参与了胆汁酸代谢的调节。

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.