Cholesteryl ester transfer protein (CETP) facilitates the net transfer of cholesteryl esters (CEs) and TGs between lipoproteins, impacting the metabolic fate of these lipoproteins. Previous studies have shown that a CETP antibody can alter CETP’s preference for CE versus TG as transfer substrate, suggesting CETP substrate preference can be manipulated in vivo. Hamster and human CETPs have very different preferences for CE and TG. To assess the effect of altering CETP’s substrate preference on lipoproteins in vivo, here we expressed human CETP in hamsters. Chow-fed hamsters received adenoviruses expressing no CETP, hamster CETP, or human CETP. Plasma CETP mass increased 2-fold in both the hamster and human CETP groups. Although animals expressing human CETP still had low levels of hamster CETP, the CE versus TG preference of their plasma CETP was similar to that of the human ortholog. Hamster CETP overexpression had little impact on lipoproteins. However, expression of human CETP reduced HDL up to 50% and increased VLDL cholesterol 2.5-fold. LDL contained 20% more CE, whereas HDL CE was reduced 40%, and TG increased 6-fold. The HDL3:HDL2 ratio increased from 0.32 to 0.60. Hepatic expression of three cholesterol-related genes (LDLR, SCARB1, and CYP7A1) was reduced up to 40%. However, HDL-associated CE excretion into feces was unchanged. We conclude that expression of human CETP in hamsters humanizes their lipoprotein profile with respect to the relative concentrations of VLDL, LDL, and HDL, and the HDL3:HDL2 ratio. Altering the lipid substrate preference of CETP provides a novel approach for modifying plasma lipoproteins.

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