Targeted disruption of the murine lecithin:cholesterol acyltransferase gene is associated with reductions in plasma paraoxonase and platelet-activating factor acetylhydrolase activities but not in apolipoprotein J concentration.
Lecithin:cholesteryl acyltransferase (LCAT) deficiency resulting from targeted disruption of the Lcat gene in the mouse is associated with dramatic decreases in HDL concentration and the accumulation of nascent HDL in the plasma. We examined whether LCAT deficiency in mice is associated with a concomitant decrease in two antioxidative enzymes, paraoxonase (PON) and platelet-activating factor acetylhydrolase (PAF-AH). In control Lcat (+/+) mice both these enzymes are transported on HDL. Compared to Lcat (+/+) mice, HDL-cholesterol is reduced 94% and apoA-I, 90%, in Lcat (-/-) mice; this reduction in HDL is paralleled by a 71% decrease in PAF-AH activity and in a 58% decrease in PON activity. Apolipoprotein J (apoJ) levels, rather than being decreased, were significantly (P = 0.01) higher (36%) in Lcat (-/-) than in Lcat (+/+) mice, and the apo J/PON ratio was 3-fold greater in Lcat (-/-) than in Lcat (+/+) animals. Even though apolipoprotein A-I (apoA-I) concentration and PON activity were drastically reduced, there was no reduction in apoA-I and PON liver mRNA levels suggesting that post-transcriptional events are responsible for the reduction of plasma PON and apoA-I levels. Fast protein liquid chromatography (FPLC) revealed that in Lcat (+/+) mice both PON and PAF-AH activity is associated with large, apoA-I-containing HDL particles (9.7 nm by non-denaturing gradient gel electrophoresis) while in Lcat (-/-) mice both enzymes are associated with small 8.2 nm particles. We conclude that the concomitant reduction in HDL and apoA-I concentrations and PON and PAF-AH activities is best explained by rapid clearance of the small HDL particles found in LCAT deficiency.
Life Sciences Division, Lawrence Berkeley National Laboratory, University of California, Berkeley, CA 94729, USA.
T M
TM
Forte
M N
MN
Oda
L
L
Knoff
B
B
Frei
J
J
Suh
J A
JA
Harmony
W D
WD
Stuart
E M
EM
Rubin
D S
DS
Ng
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood; D043303:Aryldialkylphosphatase; D002784:Cholesterol / Q000097:blood; D051152:Clusterin; D004950:Esterases / Q000097:blood*; D006023:Glycoproteins / Q000378:metabolism*; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D018832:Molecular Chaperones; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics*; D010741:Phospholipases A / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
D016632:Apolipoprotein A-I; C495243:Clu protein, mouse; D051152:Clusterin; D006023:Glycoproteins; D018832:Molecular Chaperones; D010972:Platelet Activating Factor; D012333:RNA, Messenger; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase; D004950:Esterases; D010741:Phospholipases A; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D043303:Aryldialkylphosphatase