Affordable Access

Publisher Website

Differential effects of peroxisome proliferator-activated receptor activators on the mRNA levels of genes involved in lipid metabolism in primary human monocyte-derived macrophages

DOI: 10.1053/meta.2003.50100
  • Biology


Abstract Peroxisome proliferator-activated receptors (PPARs) are key regulators of macrophage lipid metabolism. We compared the effects of three PPAR activators (bezafibrate, fenofibrate, and troglitazone) on the mRNA levels of genes involved in lipid metabolism in primary human macrophages and macrophage-derived foam cells. Treatment of human macrophages for 24 hours with 100 μmol/L bezafibrate, a nonselective drug that activates the 3 PPAR subtypes (PPARα, PPARβ/δ, and PPARγ), caused an 87% (P <.01) and a 230% rise in CD36 and adipocyte fatty acid-binding protein (aP2) mRNA levels, respectively, whereas the expressions of PPARγ, PPARα, acyl-CoA oxidase, carnitine palmitoyltransferase I (CPT-I), adenosine triphosphate (ATP)-binding cassette transporter 1 (ABCA1), neutral cholesteryl ester hydrolase, and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) were not modified. However, treatment with selective PPARα (fenofibrate at 100 μmol/L) and PPARγ (troglitazone at 5 μmol/L) activators had different effects. Fenofibrate increased PPARα (62%, P <.05) and LOX-1 (180%, P <.05) mRNA levels; and troglitazone upregulated CPT-I expression (75%, P <.05). When the effects of these drugs were assessed in macrophage-derived foam cells, we found that troglitazone caused a 134% (P <.05) and a 66% (P <.01) rise in ABCA1 and CPT-I mRNA levels, respectively, whereas the 3 drugs significantly increased aP2 transcripts (about 100% induction). Given that troglitazone treatment resulted in the upregulation of genes involved in the mitochondrial β-oxidation of fatty acids (CPT-I) and in the reverse-cholesterol-transport pathway (ABCA1), we subsequently determined whether these changes affected intracellular cholesterol ester accumulation. In macrophage-derived foam cells a significant reduction (32%, P <.01) was observed in intracellular cholesterol accumulation after troglitazone, but not after bezafibrate or fenofibrate treatment. Since CPT-I inhibition promotes cholesterol incorporation into cholesteryl esters in macrophages, study is now needed on whether CPT-I induction by troglitazone may reduce the availability of fatty acids for synthesizing cholesterol esters, leading to less foam cell formation. © 2003 Elsevier Inc. All rights reserved.

There are no comments yet on this publication. Be the first to share your thoughts.