Phospholipid transfer protein gene knock-out mice have low high density lipoprotein levels, due to hypercatabolism, and accumulate apoA-IV-rich lamellar lipoproteins

Phospholipid transfer protein gene knock-out (Pltp KO) mice have defective transfer of very low density Lipoprotein (VLDL) phospholipids into high den sity lipoprotein (HDL) and markedly decreased HDL levels (Jiang et al, 1999 ,J, Clin, Invest. 103: 907-914), These animals also accumulated VLDL- and L DL-sized lipoproteins on a high saturated fat diet. The goals of this study were to further characterize the abnormal Lipoproteins of Pltp KO mice and to determine the mechanisms responsible for low HDL levels. A lipoprotein fraction enriched in lamellar structures was isolated from the low density lipoprotein (LDL) region and was shown to be phospholipid- and free cholest erol-rich and to have apoA-IV (55%) and apoE (25%) as major apolipoproteins , The lamellar lipoproteins accumulating in these mice probably represent s urface material derived from triglyceride-rich lipoproteins (TRL). The HDL was found to be protein-rich (primarily apoA-I) and specifically depleted i n phosphatidylcholine (PC) (28% in wild-type mice (WT) vs. 15% in Pltp KO m ice, P < 0.001), Unexpectedly, turnover studies using autologous HDL reveal ed a profound 4-fold increase in the catabolism of HDL protein and choleste ryl ester in Pltp KO mice compared to wild-type, with minor differences in synthesis rates. Ln contrast, injection of WT mouse HDL into Pltp KO mice s howed only a 2-fold increase in fractional catabolism, Reminiscent of the d efect in Tangier disease, the failure of transfer of PC from TRL into the H DL fraction results in dramatic hypercatabolism of HDL. jlr These results s uggest that defective phospholipid transfer from TRL into HDL, arising from decreased lipolysis or decreased PLTP activity, could lead to hypoalphalip oproteinemia characterized by hypercatabolism of HDL protein.