Peroxisome proliferator-activated receptors (PPARs) have been implicated in metabolic diseases, such as obesity, diabetes, and atherosclerosis, due to their activity in liver and adipose tissue on genes involved in lipid and glucose homeostasis. Here, we show that the PPAR␣ and PPAR␥ forms are expressed in differentiated human monocyte-derived macrophages, which participate in inflammation control and atherosclerotic plaque formation. Whereas PPAR␣ is already present in undifferentiated monocytes, PPAR␥ expression is induced upon differentiation into macrophages. Immunocytochemistry analysis demonstrates that PPAR␣ resides constitutively in the cytoplasm, whereas PPAR␥ is predominantly nuclear localized. Transient transfection experiments indicate that PPAR␣ and PPAR␥ are transcriptionally active after ligand stimulation. Ligand activation of PPAR␥, but not of PPAR␣, results in apoptosis induction of unactivated differentiated macrophages as measured by the TUNEL assay and the appearance of the active proteolytic subunits of the cell death protease caspase-3. However, both PPAR␣ and PPAR␥ ligands induce apoptosis of macrophages activated with tumor necrosis factor ␣/interferon ␥. Finally, PPAR␥ inhibits the transcriptional activity of the NFB p65/RelA subunit, suggesting that PPAR activators induce macrophage apoptosis by negatively interfering with the anti-apoptotic NFB signaling pathway. These data demonstrate a novel function of PPAR in human macrophages with likely consequences in inflammation and atherosclerosis.

Our data demonstrate that CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and induced by PPAR activation, identifying a potential role for PPARs in cholesterol homeostasis in atherosclerotic lesion macrophages.

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...

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