REMODELING OF LIPOPROTEINS IN TRANSGENIC MICE EXPRESSING HUMAN CHOLESTERYL ESTER TRANSFER PROTEIN

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-fetoprot ein enhancer and mouse albumin gene promoter and was expressed exclusi vely in the liver. The level of human CETP activity in transgenic mous e 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 HD L cholesterol levels in plasma from female and male transgenic mice, r espectively, when compared to controls. In addition, multiple alterati ons in mouse lipoprotein composition were observed in the transgenic m ice. Diminished HDL cholesterol levels and disappearance of the apo E- rich HDL, moiety account for the dramatic reduction in plasma choleste rol. The decrease in HDL cholesterol was accompanied by a marked reduc tion in HDL particle size and apo A-I content. The cholesterol content and the size of LDL particles increased, but only modestly, in transg enic mouse plasma. In conclusion, human CETP induces a significant rem odelling of mouse lipoproteins which results in dramatic reduction in plasma cholesterol levels.