Peroxisome proliferator-activated receptor-gamma (PPAR gamma) is a nuclear transcription factor involved in lipid metabolism that is constitutively expressed in the alveolar macrophages of healthy individuals. PPAR gamma has recently been implicated in the catabolism of surfactant by alveolar macrophages, specifically the cholesterol component of surfactant while the mechanism remains unclear. Studies from other tissue macrophages have shown that PPAR gamma regulates cholesterol influx, efflux, and metabolism. PPAR gamma promotes cholesterol efflux through the liver X receptor-alpha (LXR alpha) and ATP-binding cassette G1 (ABCG1). We have recently shown that macrophage-specific PPAR gamma knockout (PPAR gamma KO) mice accumulate cholesterol-laden alveolar macrophages that exhibit decreased expression of LXR alpha and ABCG1 and reduced cholesterol efflux. We hypothesized that in addition to the dysregulation of these cholesterol efflux genes, the expression of genes involved in cholesterol synthesis and influx was also dysregulated and that replacement of PPAR gamma would restore regulation of these genes. To investigate this hypothesis, we have utilized a Lentivirus expression system (Lenti-PPAR gamma) to restore PPAR gamma expression in the alveolar macrophages of PPAR gamma KO mice. Our results show that the alveolar macrophages of PPAR gamma KO mice have decreased expression of key cholesterol synthesis genes and increased expression of cholesterol receptors CD36 and scavenger receptor A-I (SRA-I). The replacement of PPAR gamma (1) induced transcription of LXR alpha and ABCG1; (2) corrected suppressed expression of cholesterol synthesis genes; and (3) enhanced the expression of scavenger receptors CD36. These results suggest that PPAR gamma regulates cholesterol metabolism in alveolar macrophages. (C) 2010 Elsevier Inc. All rights reserved.