Liver phospholipid transfer protein (PLTP) expression with a PLTP-null background promotes very low-density lipoprotein production in mice

Abstract

It is known that plasma phospholipid transfer protein (PLTP) activity influences lipoprotein metabolism. The liver is one of the major sites of lipoprotein production and degradation, as well as of PLTP expression. To address the impact of liver-expressed PLTP on lipoprotein metabolism, we created a mouse model that expresses PLTP in the liver acutely and specifically, with a PLTP-null background. This approach in mouse model preparations can also be used universally for evaluating the function of many other genes in the liver. We found that liver PLTP expression dramatically increases plasma levels of non-high-density lipoprotein (HDL) cholesterol (2.7-fold, P < 0.0001), non-HDL phospholipid (2.5-fold, P < 0.001), and triglyceride (51%, P < 0.01), but has no significant influence on plasma HDL lipids compared with controls. Plasma apolipoprotein (apo)B levels were also significantly increased in PLTP-expressing mice (2.2-fold, P < 0.001), but those of apoA-I were not. To explore the mechanism involved, we examined the lipidation and secretion of nascent very low-density lipoprotein (VLDL), finding that liver PLTP expression significantly increases VLDL lipidation in hepatocyte microsomal lumina, and also VLDL secretion into the plasma. It is possible to prepare a mouse model that expresses the gene of interest only in the liver, but not in other tissues. Our results suggest, for the first time, that the major function of liver PLTP is to drive VLDL production and makes a small contribution to plasma PLTP activity.