Regulation of reverse cholesterol transport and biliary lipid secretion by phosphatidylcholine transfer protein
Wu, Michele K.
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Reverse cholesterol transport is the metabolic pathway for movement of excess cholesterol from peripheral tissues to liver by HDL for secretion into bile. Phosphatidylcholine transfer protein (PC-TP) is a cytosolic lipid transfer protein that catalyzes inter-membrane transfer of phosphatidylcholines, the principal phospholipid of HDL particles and biliary vesicles. Suggestive of a key role in reverse cholesterol transport, PC-TP is highly expressed in liver. To test the hypothesis that PC-TP participates in hepatocellular trafficking of phosphatidylcholines for secretion as HDL and biliary vesicles, we used Pctp (-/-) and wild type littermate control mice. Whereas the absence of PC-TP did not reduce the biliary secretion of phospholipid or cholesterol in chow-fed mice, the response of biliary lipid secretion to a dietary cholesterol challenge was markedly impaired. In plasma, phosphatidylcholine concentrations were reduced in both chow and cholesterol fed Pctp (-/-) mice. Consistent with abnormal HDL metabolism in the absence of PC-TP, there was an accumulation in plasma of small alpha- and pre-beta-migrating HDL particles and decreased hepatic clearance of HDL cholesterol. In livers of chow fed Pctp (-/-) mice, compensatory changes in key regulatory enzymes defended against changes in membrane cholesterol contents. However, in response to a dietary cholesterol challenge, there was marked accumulation of membrane cholesterol in liver. Taken together, these data support a key role for PC-TP in reverse cholesterol transport, as well as in hepatic cholesterol homeostasis.