The peroxisome proliferator-activated receptors (PPARs) are a family of fatty acid-activated transcription factors which control lipid homeostasis and cellular differentiation. PPAR␣ (NR1C1) controls lipid oxidation and clearance in hepatocytes and PPAR␥ (NR1C3) promotes preadipocyte differentiation and lipogenesis. Drugs that activate PPAR␣ are effective in lowering plasma levels of lipids and have been used in the management of hyperlipidemia. PPAR␥ 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␦ (NR1C2) and the physiological roles of PPAR␦ are unclear. In this report we demonstrate that the expression of PPAR␦ is increased during the differentiation of human macrophages in vitro. In addition, a highly selective agonist of PPAR␦ (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␦ 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 PPAR␦ and have confirmed that PPAR␦ is a powerful promoter of macrophage lipid accumulation. These data suggest that PPAR␦ may play a role in the pathology of diseases associated with lipidfilled macrophages, such as atherosclerosis, arthritis, and neurodegeneration.

No abstract

No abstract

No abstract

No abstract