Remodelling of lipoproteins in transgenic mice expressing human cholesteryl ester transfer protein.

Abstract

Cholesteryl ester transfer protein (CETP) facilitates the transfer of reciprocal exchange of neutral lipids between lipoproteins. To better understand the function of CETP and its role in atherogenic pathways, transgenic mice which express human CETP were generated. The transgene encoding human CETP was under the control of the mouse alpha-fetoprotein enhancer and mouse albumin gene promoter and was expressed exclusively in the liver. The level of human CETP activity in transgenic mouse plasmas was found to be 1- to 5-fold greater than in normolipidemic human plasma. Human CETP induced an approx. 30 and 40% reduction of HDL cholesterol levels in plasma from female and male transgenic mice, respectively, when compared to controls. In addition, multiple alterations in mouse lipoprotein composition were observed in the transgenic mice. Diminished HDL cholesterol levels and disappearance of the apo E-rich HDL1 moiety account for the dramatic reduction in plasma cholesterol. The decrease in HDL cholesterol was accompanied by a marked reduction in HDL particle size and apo A-I content. The cholesterol content and the size of LDL particles increased, but only modestly, in transgenic mouse plasma. In conclusion, human CETP induces a significant remodelling of mouse lipoproteins which results in dramatic reduction in plasma cholesterol levels.