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

To determine the physiological role of apolipopro- tein (apo) A-IV, knockout mice were created by gene tar- geting 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-111 RNA levels and a similar reduction in the plasma apoC-111 level. Complementation analysis, via crossbreeding of a mouse apoC-I11 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-I11 and not apoA-IV. ApoA-N knockout mice had normal growth, feeding behavior, and lipid absorption, except male mice showed increased food in- take in the 2 h after an 18-h fast, suggesting that under some circumstances apoA-IV might serve as a satiety fact0r.a In summary, studies in apoA-IV-induced mutant mice have dem- onstrated a role for apoA-IV in increasing HDL cholesterol by inhibiting HDL cholestexyl ester FCR yet argue against the apolipoprotein as an overall important mediator of lipid