APOLIPOPROTEIN-A-I METABOLISM IN CHOLESTERYL ESTER TRANSFER PROTEIN TRANSGENIC MICE - INSIGHTS INTO THE MECHANISMS RESPONSIBLE FOR LOW PLASMA HIGH-DENSITY-LIPOPROTEIN LEVELS

Expression of simian cholesteryl ester transfer protein (CETP) in C57B L/6 mice causes the animals' high density lipoprotein (HDL) levels to decrease. The purpose of these studies was to determine how CETP expre ssion caused that reduction. Chemical analysis showed that the HDL of the CETP transgenic mice had about twice as much triglyceride and only about 60% as much cholesteryl ester as the HDL from the C57BL/6 mice. Both strains of mouse had high levels of a circulating lipase. When p lasma from the mice was incubated at 37 degrees C for 5 h, the triglyc erides in the HDL were hydrolyzed, and apoA-I was shed from the partic le. However, apoA-I was shed from the CETP HDL more rapidly than it wa s shed from the C57BL/6 HDL. Because ''free'' apoA-I is rapidly cleare d by the kidney, increased production of free apoA-I would be expected to shorten the average life span of apoA-I in the mouse. Kinetic anal yses indicated that the life span of apoA-I was significantly reduced in the CETP transgenic mice. It was concluded that CETP expression enr iched the core of the HDL with triglyceride, which rendered it vulnera ble to lipolysis, causing apoA-I to be shed from the particle. That-sh ortened the life span of apoA-I in the CETP mice, which led to lower p lasma levels of the protein.