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

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的生理学作用，我们制造了Stard 10基因敲除小鼠（Stard 10 ^-/-）并研究了它们的表型，结果发现，在Stard 10 ^-/-小鼠中，肝脏的磷脂酰胆碱含量和胆汁的磷脂酰胆碱分泌都没有改变。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。

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.