The role of hepatic phospholipid transfer protein in lipoprotein metabolism.

Abstract

Atherosclerosis is the leading cause of death in western countries. Lipoprotein metabolism is closely related with the disease. ApoB-containing lipoproteins (BLp) are atherogenic particles, while, high density lipoproteins (HDL) are anti-atherogenic. Phospholipids Transfer Protein (PLTP) activity has important impacts on BLp and HDL homeostasis. Animal studies, including general knock out (KO) and transgenic approaches; have shown pro-atherogenic properties for PLTP. However, the tissue specific function of PLTP remains mostly unknown. The liver is one of the critical organs for lipoprotein metabolism and is also a major source for PLTP expression. To address the impact of liver-specific PLTP on lipoprotein metabolism, we created two mouse models which either express PLTP specifically in the liver on a PLTP-null background or lack PLTP in the liver (liver-specific PLTP KO) in a wild type background. In both models, our findings show that the liver has a 25% contribution into total plasma PLTP activity and liver-specific PLTP is highly involved in BLp and HDL production by hepatocytes. We found that hepatic ablation of PLTP leads to a significant decrease in plasma PLTP activity, HDL-cholesterol, HDL-phospholipids, non-HDL-cholesterol, non-HDL-phospholipids, apoA-I, and apoB levels. In addition, nuclear magnetic resonance (NMR) examination of lipoproteins showed that hepatic PLTP deficiency decreases HDL and apoB-containing particle numbers, as well as the VLDL particle size which was confirmed by electron microscopy. However, liver-specific PLTP expression results in a remarkable increase in plasma levels of BLp, as well as a slight increase in HDL levels. In order to unravel the mechanism, we evaluated the apoB and triglyceride production after blocking the clearance of the particles. We found that liver-specific PLTP increases apoB (both apo48 and apoB100) and triglyceride (TG) secretion. To investigate the role of liver PLTP in HDL production, we cultured primary hepatocytes from our knockout and wild type mice and tested their ability to form nascent HDL particles in the presence and absence of exogenous PLTP. We found that PLTP activity, as opposed to heat inactivated PLTP, promotes nascent HDL production through ABCA1-mediated pathway since ablation of ABCA1 tremendously diminished HDL production and the presence of active PLTP had no effect. We also showed that PLTP closely interact with ABCA1 in order to enhance HDL formation. Taken together, our results indicate that liver-generated PLTP promotes both BLp and HDL production by hepatocytes. In addition, the liver makes a 25% contribution to the total plasma PLTP activity, and thus ablation of liver PLTP may influence lipoprotein metabolism in the plasma.