Hepatic CTP:phosphocholine cytidylyltransferase-α is a critical predictor of plasma high density lipoprotein and very low density lipoprotein

CTP:phosphocholine cytidylyltransferase (CT) is the key regulatory enzyme in the CDP-choline pathway for the biosynthesis of phosphatidylcholine (PC). We previously generated a mouse in which the hepatic CT alpha gene was specifically inactivated by the cre/loxP procedure. In CT alpha knock-out mice, plasma high density lipoprotein (HDL) and very low density lipoprotein (VLDL) levels were markedly lower than in wild type mice (Jacobs, R.L., Devlin, C., Tabas, I., and Vance, D. E. (2004) J. Biol. Chem. 279, 47402-47410.) To investigate the mechanism(s) responsible for the decrease in plasma lipoprotein levels, we isolated primary hepatocytes from knock-out and wild type mice. ABCA1 expression was reduced in knock-out hepatocytes and apoAI-dependent cholesterol, and PC efflux was impaired. When knock-out hepatocytes were infected with an adenovirus expressing CT alpha, apoAI-dependent PC efflux returned partially, whereas cholesterol efflux and ABCA1 levels were not restored to normal levels. Adenoviral expression of CT alpha did not increase VLDL secretion in knock-out hepatocytes, even though cellular PC levels returned to normal. However, in vivo adenoviral delivery of CT alpha normalized plasma HDL and VLDL levels in knock-out mice. The observations demonstrate that hepatic PC biosynthesis is a key player in maintaining plasma VLDL and HDL, and further underscores the importance of the liver in HDL formation.