PPARgamma regulates the expression of cholesterol metabolism genes in alveolar macrophages.
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear transcription factor involved in lipid metabolism that is constitutively expressed in the alveolar macrophages of healthy individuals. PPARgamma 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 PPARgamma regulates cholesterol influx, efflux, and metabolism. PPARgamma promotes cholesterol efflux through the liver X receptor-alpha (LXRalpha) and ATP-binding cassette G1 (ABCG1). We have recently shown that macrophage-specific PPARgamma knockout (PPARgamma KO) mice accumulate cholesterol-laden alveolar macrophages that exhibit decreased expression of LXRalpha 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 PPARgamma would restore regulation of these genes. To investigate this hypothesis, we have utilized a Lentivirus expression system (Lenti-PPARgamma) to restore PPARgamma expression in the alveolar macrophages of PPARgamma KO mice. Our results show that the alveolar macrophages of PPARgamma 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 PPARgamma (1) induced transcription of LXRalpha and ABCG1; (2) corrected suppressed expression of cholesterol synthesis genes; and (3) enhanced the expression of scavenger receptors CD36. These results suggest that PPARgamma regulates cholesterol metabolism in alveolar macrophages.
Baker
Anna D
AD
Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, East Carolina University, Greenville, NC 27834, USA.
Malur
Anagha
A
Barna
Barbara P
BP
Kavuru
Mani S
MS
Malur
Achut G
AG
Thomassen
Mary Jane
MJ
D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D050356:Lipid Metabolism / Q000235:genetics*; D008074:Lipoproteins / Q000235:genetics; D000071518:Liver X Receptors; D016676:Macrophages, Alveolar / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors / Q000235:genetics; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics; D015854:Up-Regulation
C487540:ABCG1 protein, mouse; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D008074:Lipoproteins; D000071518:Liver X Receptors; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol