Abstract
Phosphatidylcholine transfer protein (PC-TP) is a cytosolic lipid transfer protein that is highly expressed in liver and catalyzes intermembrane transfer of phosphatidylcholines in vitro. To explore a role for PC-TP in the hepatocellular trafficking of biliary phosphatidylcholines, we characterized biliary lipid secretion using Pctp(-/-) and wild-type littermate control mice with C57BL/6J and FVB/NJ genetic backgrounds, which express PC-TP at relatively high and low levels in liver, respectively. Eight-week-old male Pctp(-/-) and wild-type mice were fed a chow diet or a lithogenic diet, which served to upregulate biliary lipid secretion. In chow-fed mice, the absence of PC-TP did not reduce biliary phospholipid secretion or alter the phospholipid composition of biles. However, the responses in secretion of biliary phospholipids, cholesterol, and bile salts to the lithogenic diet were impaired in Pctp(-/-) mice from both genetic backgrounds. Alterations in biliary lipid secretion could not be attributed to transcriptional regulation of the expression of canalicular membrane lipid transporters, but possibly to a defect in their trafficking to the canalicular membrane. These findings support a role for PC-TP in the response of biliary lipid secretion to a lithogenic diet, but not specifically in the hepatocellular transport and secretion of phosphatidylcholines.
Highlights
Phosphatidylcholine transfer protein (PC-TP) is a cytosolic lipid transfer protein that is highly expressed in liver and catalyzes intermembrane transfer of phosphatidylcholines in vitro
Using PctpϪ/Ϫ mice bred onto two distinct genetic backgrounds, we provide evidence for impaired biliary lipid secretion in PctpϪ/Ϫ mice in response to a lithogenic diet containing sufficient cholesterol content to promote the formation of cholesterol gallstones
Susceptibility to cholesterol gallstones upon challenge with a lithogenic diet is a readily detectable phenotype that differs dramatically among inbred strains of mice [23] and in part reflects the biliary response to dietary cholesterol
Summary
Phosphatidylcholine transfer protein (PC-TP) is a cytosolic lipid transfer protein that is highly expressed in liver and catalyzes intermembrane transfer of phosphatidylcholines in vitro. Using mice with homozygous disruption of the Pctp gene (PctpϪ/Ϫ), van Helvoort et al [14] tested a role for PC-TP in biliary lipid secretion by mice They observed that biliary phosphatidylcholine secretion occurred normally in PctpϪ/Ϫ mice under basal conditions and when biliary secretion rates were driven to higher rates by intravenous infusion of a hydrophilic bile salt [14]. This finding excluded PC-TP as an exclusive mechanism for hepatocellular selection and transport of biliary phosphatidylcholines, it did not eliminate the possibility that another pathway was able to compensate under these specific experimental conditions. Considering that secretion of biliary phospholipids is upregulated in mice by dietary cholesterol supplementation
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