Regulation of reverse cholesterol transport and biliary lipid secretion by phosphatidylcholine transfer protein

Abstract

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.