Decreased HDL cholesterol levels but normal lipid absorption, growth, and feeding behavior in apolipoprotein A-IV knockout mice.
To determine the physiological role of apolipoprotein (apo) A-IV, knockout mice were created by gene targeting in embryonic stem cells. In apoA-IV knockout mice, plasma cholesterol and triglyceride levels were reduced 25% and 44%, respectively, compared with controls. These changes were accounted for by decreased high density (HDL) and very low density lipoprotein (VLDL) levels, respectively, and metabolic studies indicated increased HDL-cholesteryl ester (CE) fractional catabolic rate (FCR) and reduced VLDL transport rate (TR), respectively. ApoA-IV knockout mice had greater than 70% reductions in both hepatic and intestinal apoC-III RNA levels and a similar reduction in the plasma apoC-III level. Complementation analysis, via crossbreeding of a mouse apoC-III transgene onto both the normal and apoA-IV knockout backgrounds, clearly demonstrated that the low triglyceride (VLDL) level in the apoA-IV knockout mice was due to alterations in apoC-III and not apoA-IV. ApoA-IV knockout mice had normal growth, feeding behavior, and lipid absorption, except male mice showed increased food intake in the 2 h after an 18-h fast, suggesting that under some circumstances apoA-IV might serve as a satiety factor. In summary, studies in apoA-IV-induced mutant mice have demonstrated a role for apoA-IV in increasing HDL cholesterol by inhibiting HDL cholesteryl ester FCR yet argue against the apolipoprotein as an overall important mediator of lipid absorption/metabolism.
Weinstock
P H
PH
Laboratory of Biochemical Genetics and Metabolism, Rockefeller University, New York, NY 10021, USA.
Bisgaier
C L
CL
Hayek
T
T
Aalto-Setala
K
K
Sehayek
E
E
Wu
L
L
Sheiffele
P
P
Merkel
M
M
Essenburg
A D
AD
Breslow
J L
JL
D000818:Animals; D016632:Apolipoprotein A-I / Q000097:blood / Q000235:genetics; D053305:Apolipoprotein C-III; D001054:Apolipoproteins A / Q000172:deficiency* / Q000235:genetics; D001056:Apolipoproteins C / Q000235:genetics; D002788:Cholesterol Esters / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood* / Q000378:metabolism; D004041:Dietary Fats / Q000493:pharmacokinetics; D004435:Eating; D005247:Feeding Behavior; D005260:Female; D015870:Gene Expression; D006128:Growth; D007408:Intestinal Absorption; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D015430:Weight Gain
D016632:Apolipoprotein A-I; D053305:Apolipoprotein C-III; D001054:Apolipoproteins A; D001056:Apolipoproteins C; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D004041:Dietary Fats; C059714:HDL cholesteryl ester; D008055:Lipids; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D012333:RNA, Messenger; C022205:apolipoprotein A-IV