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

Abstract The peroxisome proliferator-activated receptors (PPARs) are a family of fatty acid-activated transcription factors which control lipid homeostasis and cellular differentiation. PPARα (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPARγ (NR1C3) promotes preadipocyte differentiation and lipogenesis. Drugs that activate PPARα are effective in lowering plasma levels of lipids and have been used in the management of hyperlipidemia. PPARγ agonists increase insulin sensitivity and are used in the management of type 2 diabetes. In contrast, there are no marketed drugs that selectively target PPARδ (NR1C2) and the physiological roles of PPARδ are unclear. In this report we demonstrate that the expression of PPARδ is increased during the differentiation of human macrophagesin vitro. In addition, a highly selective agonist of PPARδ (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. PPARδ 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 PPARδ and have confirmed that PPARδ is a powerful promoter of macrophage lipid accumulation. These data suggest that PPARδ may play a role in the pathology of diseases associated with lipid-filled macrophages, such as atherosclerosis, arthritis, and neurodegeneration.