Two lines of transgenic mice, hAIItg-␦ and hAIItg-, expressing human apolipoprotein (apo)A-II at 2 and 4 times the normal concentration, respectively, displayed on standard chow postprandial chylomicronemia, large quantities of very low density lipoprotein (VLDL) and low density lipoprotein (LDL) but greatly reduced high density lipoprotein (HDL). Hypertriglyceridemia may result from increased VLDL production, decreased VLDL catabolism, or both. Post-Triton VLDL production was comparable in transgenic and control mice. Postheparin lipoprotein lipase (LPL) and hepatic lipase activities decreased at most by 30% in transgenic mice, whereas adipose tissue and muscle LPL activities were unaffected, indicating normal LPL synthesis. However, VLDL-triglyceride hydrolysis by exogenous LPL was considerably slower in transgenic compared with control mice, with the apparent V max of the reaction decreasing proportionately to human apoA-II expression. Human apoA-II was present in appreciable amounts in the VLDL of transgenic mice, which also carried apoC-II. The addition of purified apoA-II in postheparin plasma from control mice induced a dose-dependent decrease in LPL and hepatic lipase activities. In conclusion, overexpression of human apoA-II in transgenic mice induced the proatherogenic lipoprotein profile of low plasma HDL and postprandial hypertriglyceridemia because of decreased VLDL catabolism by LPL. Low plasma HDL1 levels are negatively correlated with the risk of atherosclerosis. Although a number of metabolic functions of HDL have been identified, no direct link has been established between HDL functions and its antiatherogenic effect (1). In vitro studies have shown that apolipoprotein (apo)A-I, the major HDL apolipoprotein, activates reverse cholesterol transport from extrahepatic tissues to the liver (2). However, conflicting results have been reported concerning the role of apoA-II, the second most abundant HDL apolipoprotein (3, 4). Studies of transgenic mice overexpressing human apoA-I and apoA-II reported that apoA-I protected more against aortic lesions than apoA-II (3). Furthermore, HDL from transgenic mice overexpressing mouse apoA-II lost the ability of HDL to protect against low density lipoprotein (LDL) oxidation (5) and was even proinflammatory (6). Deficiency of either apoA-I (7, 8) or apoA-II (9) obtained by gene targeting technology resulted in very low plasma HDL, showing the critical importance of both apolipoproteins in maintaining the normal structure and metabolism of HDL. At present, apoA-II has been linked with HDL metabolism only, but its exact role remains to be elucidated.Studies of transgenic mice expressing human (10 -13) or murine (14, 15) apoA-II, alone or in combination with human apoA-I, apoC-III, and cholesterol ester transfer protein (16), have provided interesting information. When human apoA-II was expressed at normal levels, overall lipoprotein metabolism was not markedly modified, except for the appearance of a smaller HDL population containing solely human apoA-II (10). At...

The activity of the human apoA-II promoter is controlled by a synergistic interaction of the distal enhancer and the proximal promoter. An important role in apoA-II promoter activity is exerted by a transcription factor, designated CIIIB1, which binds to the proximal element AB and the distal elements of the enhancer, K and L. In the present communication we establish that CIIIB1 corresponds to the previously described factor, upstream stimulatory factor (USF) using the following criteria. (a) Purification of CIIIB1 by affinity chromatography provided a heat-stable protein with an apparent molecular mass of 45 kDa that cross-reacted with anti-USF1 and -USF2a antibodies; (b) CIIIB1 bound to the elements AB, K, and L was supershifted by these antibodies; (c) the heterodimer USF1/2a is the predominant form that corresponds to CIIIB1. Cotransfection experiments in HepG2 cells established the functional significance of USF in apoA-II transcription. It was found that the minimal promoter AB was transactivated by USF2a. In addition, all three E-box motifs present in elements AB, K and L are necessary for maximum transactivation by USF2a. A dominant negative form of USF2a inhibits the activity of apoA-II promoter. The USF1/2a heterodimer, which is naturally expressed in the liver, is as efficient as the USF2a homodimer in the transactivation of apoA-II promoter/enhancer constructs. Cotransfection experiments in COS-1 cells showed that hepatic nuclear factor 4 (HNF-4) synergized with USF2a in the transactivation of the apoA-II promoter. In addition, we showed that HNF-4 and USF2a bind to the enhancer cooperatively. This may account for the transcriptional synergism observed between USF and HNF-4 in the transactivation of the apoA-II promoter.

The hydrophobicity of human apolipoprotein A-II is a key regulatory factor of HDL metabolism. Due to the lower plasma apolipoprotein A-II concentration during fasting, measurements of apolipoprotein A-II in fed subjects are more relevant. More clinical studies are necessary to clarify the role of apolipoprotein A-II in well-characterized subsets of patients and in the insulin resistance syndrome.