The peroxisome proliferator-activated receptor δ promotes lipid accumulation in human macrophages

The peroxisome Proliferator-activated receptors (PPARs) are a family of fatty acid-activated transcription factors which control lipid homeostasis and cellular differentiation. PPAR alpha (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPAR gamma (NR1C3) promotes preadipocyte differentiation and lipogenesis. Drugs that activate PPAR alpha are effective in lowering plasma levels of lipids and have been used in the management of hyperlipidemia. PPAR gamma agonists increase insulin sensitivity and are used in the management of type 2 diabetes. In contrast, there are no marketed drugs that selectively target PPAR delta (NR1C2) and the physiological roles of PPAR delta are unclear. In this report we demonstrate that the expression of PPAR5 is increased during the differentiation of human macrophages in vitro. In addition, a highly selective agonist of PPAR delta (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. PPAR delta activation also represses key genes involved in lipid metabolism and efflux, ie. cholesterol 27-hydroxylase and apolipoprotein E. We have generated THP-1 sublines that overexpress PPAR delta and have confirmed that PPAR delta is a powerful promoter of macrophage lipid accumulation. These data suggest that PPAR5 may play a role in the pathology of diseases associated with lipid-filled macrophages, such as atherosclerosis, arthritis, and neurodegeneration.