COEXPRESSION OF CHOLESTERYL ESTER TRANSFER PROTEIN AND DEFECTIVE APOLIPOPROTEIN-E IN TRANSGENIC MICE ALTERS PLASMA-CHOLESTEROL DISTRIBUTION- IMPLICATIONS FOR THE PATHOGENESIS OF TYPE-III HYPERLIPOPROTEINEMIA

Despite the definite etiologic link between apolipoprotein (ape) E mut ations and type III hyperlipoproteinemia (HLP), it is not clear what a dditional factors are involved in the development of florid hyperlipid emia and how to explain the wide variability in the expression of the hyperlipidemic phenotype in carriers of receptor binding-defective apo E variants, The present study was designed to determine whether the ov erexpression of cholesteryl ester transfer protein (CETP), a plasma pr otein that transfers cholesteryl esters hom the high density lipoprote ins (HDL) to the very low density lipoproteins (VLDL) and whose activi ty is increased in hyperlipidemic states, plays a role in the developm ent of hyperlipidemia and beta-VLDL accumulation in type III HLP. We p roduced double-transgenic mice that co-expressed high levels of simian CETP and either high or low levels of a human receptor binding-defect ive apoE variant, apoE(Cys-142). We previously reported that apoE(Cys- 142) high-expresser mice showed spontaneous hyperlipidemia and accumul ation of beta-VLDL, whereas the low-expresser mice showed only a modes t increase in VLDL cholesterol. Go-expression of CETP induced a massiv e transfer of cholesteryl esters from the HDL to the VLDL in both line s of double-transgenic mice. As a result, HDL cholesterol and apoA-I l evels were reduced to about 50% of normal, VLDL cholesterol increased 2.5-fold, and the cholesteryl ester content of VLDL reached values sim ilar to those observed in human beta-VLDL. The ratio of defective to n ormal apoE in VLDL was unaffected by CETP co-expression and was higher in animals expressing high apoE levels, Finally, in spite of an incre ased accumulation of beta-VLDL in the high-expresser mice, the VLDL of the low-expresser mice maintained pre-beta mobility upon co expressio n of CETP. The results of this study demonstrate that the ratio of def ective to normal apoE on the VLDL, rather than the cholesteryl ester c ontent of VLDL, is the major factor determining the development of sev ere hyperlipidemia and the formation and accumulation of beta-VLDL in type III HLP.