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 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.
Melchior
G W
GW
Department of Metabolic Diseases Research, Upjohn Laboratories, Kalamazoo, Michigan 49001.
Castle
C K
CK
Murray
R W
RW
Blake
W L
WL
Dinh
D M
DM
Marotti
K R
KR
D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis / Q000378:metabolism*; D001053:Apolipoproteins / Q000096:biosynthesis*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D002784:Cholesterol / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters / Q000097:blood; D006023:Glycoproteins; D006801:Humans; D007700:Kinetics; D008075:Lipoproteins, HDL / Q000097:blood*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D010743:Phospholipids / Q000097:blood; D013045:Species Specificity; D013997:Time Factors; D014280:Triglycerides / Q000097:blood
D016632:Apolipoprotein A-I; D001053:Apolipoproteins; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D006023:Glycoproteins; D008075:Lipoproteins, HDL; D010743:Phospholipids; D014280:Triglycerides; D002784:Cholesterol