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.

Liver steatosis, which involves accumulation of intracytoplasmic lipid droplets, is characteristic of hepatitis C virus (HCV) infection. By use of an in vivo transgenic murine model, we demonstrate that hepatic overexpression of HCV core protein interferes with the hepatic assembly and secretion of triglyceride-rich very low density lipoproteins (VLDL). Core expression led to reduction in microsomal triglyceride transfer protein (MTP) activity and in the particle size of nascent hepatic VLDL without affecting accumulation of MTP and protein disulfide isomerase. Hepatic human apolipoprotein AII (apo AII) expression in double-core/apo AII transgenic mice diminished intrahepatic core protein accumulation and abrogated its effects on VLDL production. Apo AII and HCV core colocalized in human HCV-infected liver biopsies, thus testifying to the relevance of this interaction in productive HCV infection. Our results lead us to propose a new pathophysiological animal model for induction of viral-related steatosis whereby the core protein of HCV targets microsomal triglyceride transfer protein activity and modifies hepatic VLDL assembly and secretion.

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.

A colony of 26 chimpanzees given a fruit and vegetable diet of very low Na and high K intake were maintained in long-standing, socially stable small groups for three years. Half of them had salt added progressively to their diet during 20 months. This addition of salt within the human dietetic range caused a highly significant rise in systolic, mean and diastolic blood pressure. The change reversed completely by six months after cessation of salt. The effect of salt differed between chimpanzees, some having a large blood pressure rise and others small or no rise. These results in the species phylogenetically closest to humans bear directly on causation of human hypertension, particularly in relation to migration of preliterate people, with low Na diet, to a Western urban lifestyle with increased salt intake. The hedonic liking for salt and avid ingestion was apt during human prehistory involving hunter-gatherer-scavenger existence in the interior of continents with a scarcity of salt, but is maladaptive in urban technological life with salt cheap and freely available.

Abstract-A new polymorphism located at position Ϫ629 (CETP/Ϫ629A/C) in the promoter of the cholesteryl ester transfer protein (CETP) gene is described. The Ϫ629A allele was associated with lower CETP mass (PϽ0.0001) and higher high density lipoprotein cholesterol (PϽ0.001) than the C allele in a sample of 536 control subjects from the ECTIM study. Transfection studies in HepG2 cells with a luciferase expression vector incorporating a 777-bp fragment of the CETP promoter and containing either A or C at position Ϫ629 showed significantly lower luciferase activity with the promoter fragment of the A allele (Ϫ25%, PϽ0.05). By gel-shift assay, DNA-protein interactions were evaluated in nuclear extracts of HepG2 cells with the use of 2 probes (A or C probe) composed of 20 bp of the promoter sequence surrounding the polymorphic site. Two specific complexes of distinct migration rate were identified with the A and the C probe. Competition with an excess of oligonucleotide containing the Sp1 consensus binding site showed that a protein(s) of the Sp transcription factor family was implicated in complex formation with the A probe but not with the C probe. Incubation with specific antibodies indicated that Sp1 and Sp3 bound specifically to the A probe. We introduced mutations in the Ϫ629-Sp1 binding site to test its functionality and to define the characteristics of transcription factor binding. We showed, by gel-shift assay, that no nuclear proteins bound to the mutated sequence. Transient transfection of HepG2 cells revealed that the expression of the mutated fragment was significantly increased compared with that of the A promoter fragment (25%, PϽ0.05). The mutated fragment displayed the same activity as that of the C promoter. These results indicate that Sp1 and/or Sp3 repress CETP promoter activity, whereas nuclear factors binding the C allele are without effect on promoter expression. Key Words: cholesteryl ester transfer protein Ⅲ gene polymorphisms Ⅲ transcription factors Ⅲ ECTIM Ⅲ cardiovascular disease S everal prospective epidemiological studies have shown that elevated levels of HDL cholesterol (HDL-C) constitute an independent negative risk factor for coronary heart disease. 1 Cholesteryl ester transfer protein (CETP) plays a central role in the reverse transport of cholesterol from peripheral tissues to the liver and in the remodeling of plasma lipoproteins by promoting the transfer of cholesteryl esters from HDL to LDL and VLDL lipoproteins. 2,3 The critical role of CETP in lipoprotein metabolism is illustrated by the high levels of HDL-C observed in patients with genetic CETP deficiency. 4 In addition, elevated levels of CETP activity may contribute to an increased risk of coronary artery disease by reducing the cholesterol content of HDL relative to LDL and VLDL 5 and by promoting the formation of atherogenic, small, dense LDL in hyperlipidemic patients. 6 Several common polymorphisms have been described in the CETP gene, 7-10 most of which are associated with plasma CETP mass and HDL-C levels. 9,11,12 How...