Abstract 330: Liver-Specific Phospholipids Transfer Protein Activity Has Significant Contribution in Hepatocyte Apob-Containing Lipoprotein Production and in Plasma Lipoprotein Metabolism
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 impact 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. To address the impact of liver-specific expression of PLTP on lipoprotein metabolism, we have created two mouse models which either express PLTP specifically in the liver on a PLTP-null background or do not express PLTP in the liver (liver-specific PLTP KO) in a wild type background. In both models, our findings show that liver-specific PLTP is responsible for 25-30% of total plasma PLTP activity. Moreover, liver-specific PLTP expression model shows a remarkable increase in plasma levels of BLp, whereas liver-specific PLTP KO mice show significant reduction of BLp in plasma in compare to control group. These results further show the significant contribution of PLTP in BLp production.
We also found that HDL levels are slightly increased in the first model, while in liver-specific PLTP KO animals HDL levels are significantly decreased. In order to unravel the mechanism, we evaluated the apoB and triglyceride production rates after blocking the clearance of the particles. We found that liver-specific PLTP increases apoB (both apo48 and apoB100) and triglyceride (TG) secretion rates. Additionally, the study of the hepatocyte microsomal luminal content lipidation in the first model showed that in the presence of PLTP BLp lipidation, which reflects as higher level of TG in microsomal luminal content, is significantly higher than the control group. Our results indicate that liver-generated PLTP promotes atherogenic lipoprotein production and provides a rationale for liver-specific PLTP inhibition as a therapeutical approach for the treatment of atherosclerosis.
- © 2012 by American Heart Association, Inc.