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 (ape) A-IV, knoc kout mice were created by gene targeting in embryonic stem cells. In a poA-IV knockout mice, plasma cholesterol and triglyceride levels were reduced 25% and 44%, respectively, compared with controls. These chang es were accounted for by decreased high density (HDL) and very low den sity lipoprotein (VLDL) levels, respectively, and metabolic studies in dicated increased HDL-cholesteryl ester (CE) fractional catabolic rate (FCR) and reduced VLDL transport rate (TR), respectively. ApoA-IV kno ckout mice had greater than 70% reductions in both hepatic and intesti nal apoC-III RNA levels and a similar reduction in the plasma apoC-III level. Complementation analysis, via crossbreeding of a mouse apoC-II I transgene onto both the normal and apoA-IV knockout backgrounds, cle arly demonstrated that the low triglyceride (VLDL) level in the apoA-I V knockout mice was due to alterations in apoC-III and not apoA-IV. Ap oA-IV knockout mice had normal growth, feeding behavior, and lipid abs orption, except male mice showed increased food intake in the 2 h afte r an 18-h fast, suggesting that under some circumstances apoA-IV might serve as a satiety factor. In summary, studies in apoA-IV-induced mut ant mice have demonstrated a role for apoA-IV in increasing HDL choles terol by inhibiting HDL cholesteryl ester FCR yet argue against the ap olipoprotein as an overall important mediator of lipid absorption/meta bolism.