Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The peroxisome proliferator-activated receptors (PPARs) are a family of fatty acid-activated transcription factors which control lipid homeostasis and cellular differentiation. PPARalpha (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPARgamma (NR1C3) promotes preadipocyte differentiation and lipogenesis. Drugs that activate PPARalpha are effective in lowering plasma levels of lipids and have been used in the management of hyperlipidemia. PPARgamma agonists increase insulin sensitivity and are used in the management of type 2 diabetes. In contrast, there are no marketed drugs that selectively target PPARdelta (NR1C2) and the physiological roles of PPARdelta are unclear. In this report we demonstrate that the expression of PPARdelta is increased during the differentiation of human macrophages in vitro. In addition, a highly selective agonist of PPARdelta (compound F) promotes lipid accumulation in primary human macrophages and in macrophages derived from the human monocytic cell line, THP-1. Compound F increases the expression of genes involved in lipid uptake and storage such as the class A and B scavenger receptors (SRA, CD36) and adipophilin. PPARdelta activation also represses key genes involved in lipid metabolism and efflux, i.e. cholesterol 27-hydroxylase and apolipoprotein E. We have generated THP-1 sublines that overexpress PPARdelta and have confirmed that PPARdelta is a powerful promoter of macrophage lipid accumulation. These data suggest that PPARdelta may play a role in the pathology of diseases associated with lipid-filled macrophages, such as atherosclerosis, arthritis, and neurodegeneration.
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PMID:The peroxisome proliferator-activated receptor delta promotes lipid accumulation in human macrophages. 1155 74

Oxidized low-density lipoprotein (oxLDL), a marker of hyperlipidemia, plays a pivotal role in the development of atherosclerosis through the induction of macrophage-derived foam cell formation and thereafter apoptosis. Previous studies have indicated that silica nanoparticle (SiNPs) may exert a proatherogenic role, which could induce endothelial dysfunction, and monocytes infiltration. However, little is known about SiNPs' effects on macrophage-derived foam cell formation and apoptosis in the pathogenesis of atherosclerosis. In this study, we investigated the effects of SiNPs and oxLDL coexposure on macrophage-derived lipid metabolism, foam cell and apoptosis by using Raw264.7 cells. As a result, SiNPs enhanced cytotoxicity, apoptosis, and lipid accumulation upon oxLDL stimulation. Furthermore, quantitative determination of the expression levels of genes involved in cholesterol influx or efflux showed significantly up-regulated expressions of CD36 and SRA, whereas down-regulated expressions of ATP-binding cassette A1 (ABCA1), ABCG1, and SRB1 in oxLDL-treated macrophages, especially upon the co-exposure with SiNPs. It indicated that SiNPs promoted lipid accumulation in macrophage cells through not only facilitating cholesterol influx but also inhibiting cholesterol efflux. Endoplasmic reticulum (ER) is specialized for the production, modification, even trafficking of lipids. Interestingly, ER response was triggered upon oxLDL treatment, while SiNPs coexposure augmented the ER stress. Taken together, our results revealed that SiNPs promoted oxLDL-induced macrophage foam cell formation and apoptosis, which may be mediated by ER stress signaling. Thus we propose future researches needed for a better understanding of NPs' toxicity and their interactions with various pathophysiological conditions.
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PMID:Silica nanoparticles promote oxLDL-induced macrophage lipid accumulation and apoptosis via endoplasmic reticulum stress signaling. 2953 93