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

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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.