Decreased HDL cholesterol levels but normal lipid absorption, growth, and feeding behavior in apolipoprotein A-IV knockout mice.

TY - JOUR

T1 - Decreased HDL cholesterol levels but normal lipid absorption, growth, and feeding behavior in apolipoprotein A-IV knockout mice.

AU - Weinstock, P H

AU - Bisgaier, C L

AU - Hayek, T

AU - Aalto-Setala, K

AU - Sehayek, E

AU - Wu, L

AU - Sheiffele, P

AU - Merkel, Martin

AU - Essenburg, A D

AU - Breslow, J L

PY - 1997

Y1 - 1997

N2 - 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.

AB - 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.

M3 - SCORING: Zeitschriftenaufsatz

VL - 38

SP - 1782

EP - 1794

JO - J LIPID RES

JF - J LIPID RES

SN - 0022-2275

IS - 9

M1 - 9

ER -