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Lipoprotein lipase (LPL) hydrolyzes triglycerides in plasma lipoproteins causing release of fatty acids for metabolic purposes in muscles and adipose tissue. LPL in macrophages in the artery wall may, however, promote foam cell formation and atherosclerosis. Angiopoietin-like protein (ANGPTL) 4 inactivates LPL and ANGPTL4 expression is controlled by peroxisome proliferator-activated receptors (PPAR). The mechanisms for inactivation of LPL by ANGPTL4 was studied in THP-1 macrophages where active LPL is associated with cell surfaces in a heparin-releasable form, while LPL in the culture medium is mostly inactive. The PPAR delta agonist GW501516 had no effect on LPL mRNA, but increased ANGPTL4 mRNA and caused a marked reduction of the heparin-releasable LPL activity concomitantly with accumulation of inactive, monomeric LPL in the medium. Intracellular ANGPTL4 was monomeric, while dimers and tetramers of ANGPTL4 were present in the heparin-releasable fraction and medium. GW501516 caused an increase in the amount of ANGPTL4 oligomers on the cell surface that paralleled the decrease in LPL activity. Actinomycin D blocked the effects of GW501516 on ANGPTL4 oligomer formation and prevented the inactivation of LPL Antibodies against ANGPTL4 interfered with the inactivation of LPL. We conclude that inactivation of LPL in THP-1 macrophages primarily occurs on the cell surface where oligomers of ANGPTL4 are formed. (c) 2012 Elsevier Inc. All rights reserved.

The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in energy homeostasis. Their natural ligands are fatty acids and there are three different PPAR isoforms; PPARA, PPARG and PPARD. They are encoded by separate genes and have distinct functions, due to different tissue expression and affinity for ligands. PPARA controls genes involved in fatty acid oxidation, PPARG regulates genes important for fatty acid storage, and PPARD controls genes implicated in lipid oxidation and lipoprotein metabolism. Primates and humans treated with a PPARD agonist (GW501516) resulted in improved insulin sensitivity, increased HDL and decreased LDL cholesterol levels, making it a putative drug candidate for treatment of metabolic disease. PPARD has recently been assigned a beneficial role in macrophages, by inducing a switch from proinflammatory (M1) to antiinflammatory (M2) macrophages. To characterize additional target genes of PPARD involved in the lipoprotein metabolism, the effect of PPARD activation on the apolipoprotein A-II (apoA-II) gene was investigated in human hepatoma cells. ApoA-II is one of the major proteins in the HDL particles. Treatment with GW501516 increased apoA-II promoter activity and mRNA levels in hepatoma cell lines. A site located at -737/-717 in the promoter was identified as the functional PPAR response element (PPRE). These results suggest that increased expression of the apoA-II gene is one of the reasons for the beneficial effects on lipoprotein metabolism after treatment with the PPARD agonist. To investigate whether PPARs could regulate the alanine aminotransferase (ALT) genes, the effect of PPARA, G and D agonist treatment was studied. ALT activity in plasma is used as a marker for hepatotoxicity in humans. During a clinical trial with the PPARA ligand, AZD4619, the plasma ALT activity increased in some patients and in vitro studies showed that ALT1 protein and mRNA expression was induced by treat

Udgivelsesdato: 2010-Jan, Promoter polymorphisms in microsomal triglyceride transfer protein (MTTP) have been associated with decreased plasma lipids but an increased risk for ischemic heart disease (IHD), indicating that MTTP influences the susceptibility for IHD independent of plasma lipids. The objective of this study was to characterize the functional promoter polymorphism in MTTP predisposing to IHD and its underlying mechanism. Use of pyrosequencing technology revealed that presence of the minor alleles of the promoter polymorphisms -493G>T and -164T>C result in lower transcription of MTTP in vivo in the heart, liver, and macrophages. In vitro experiments indicated that the minor -164C allele mediates the lower gene expression and that C/EBP binds to the polymorphic region in an allele-specific manner. Furthermore, homozygous carriers of the -164C were found to have increased risk for IHD as shown in a case-control study including a total of 544 IHD patients and 544 healthy control subjects. We concluded that carriers of the minor -164C allele have lower expression of MTTP in the heart, mediated at least partly by the transcription factor CCAAT/enhancer binding protein, and that reduced concentration of MTTP in the myocardium may contribute to IHD upon ischemic damage.