Abstract
Expression of simian cholesteryl ester transfer protein (CETP) in C57BL/6 mice causes the animals' high density lipoprotein (HDL) levels to decrease. The purpose of these studies was to determine how CETP expression 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 plasma from the mice was incubated at 37 degrees C for 5 h, the triglycerides in the HDL were hydrolyzed, and apoA-I was shed from the particle. However, apoA-I was shed from the CETP HDL more rapidly than it was shed from the C57BL/6 HDL. Because "free" apoA-I is rapidly cleared 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 analyses indicated that the life span of apoA-I was significantly reduced in the CETP transgenic mice. It was concluded that CETP expression enriched the core of the HDL with triglyceride, which rendered it vulnerable to lipolysis, causing apoA-I to be shed from the particle. That shortened the life span of apoA-I in the CETP mice, which led to lower plasma levels of the protein.
Highlights
Expression of simian cholesteryl ester transfer pro- various components move into or out of the particle and are tein (CETP) in C57BL/6 mice causes the animals’ high catabolized independently (Glass et al, 1983a, 1985)
Since apoA-I is the principal pressioncausedtharteductionC. hemicaalnalysis protein component of HDL, its life span is often equated with showed thatthe HDL of the CETP transgenic mice had that of HDL, and therelationship between plasma about twiceas much triglyceride and only abou6W t ’ as apoA-I levels and atherosclerosis is nearly the same as that much cholesteryl ester as the HDLfrom the C57BU6 between HDL cholesterol and atherosclerosis
Kinetic analy- the cynomolgus monkey, apoA-I synthesis is not amajor control ses indicated that the life span of apoA-I was significantly reducedin the CETP transgenic miceI. t wasconcluded that CETP expression enriched the core of the HDL with triglyceride, which renderedit vulnerable to lipolysis, causing apoA-I to be shed from the particle
Summary
We have previously described four linesof transgenic C57BU6 mice expressing cynomolgus monkeycholesteryel stertransferprotein (Marotti et al, 1992). Experiments 2-4 were studies to compare the mean residence timoef apoA-I in UCTP-20 mice with that in C57BU6 mice. The fractionof measure phospholipids, and the lipid-phosphorus was quantified by a the plasma radioactivity that was protein-bound was determined by modification of theBartlettprocedure(Bartlett, 1959). That value ranged between 75 and measured using a modification of the Lowry method (Peterson, 1983); 96% in samples taken during the1st day after isotope administration and SDS-PAGE andagaroseelectrophoresiswereperformedas de- and between 96 and 100% in samples taken a t 24, 48, and 72 h. Thefood was removed from the animals’ cages at 8:OO a.m., and the blood samples were takenat L O O p.m. CETP activity, determined as described previously One arbitrary unit is the CETP activity ina n equivalent volume of cynomolgus monkey plasma standard analyzed simultaneously
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