Conditional Disruption of the Peroxisome Proliferator-Activated Receptor γ Gene in Mice Results in Lowered Expression of ABCA1, ABCG1, and apoE in Macrophages and Reduced Cholesterol Efflux

Abstract

Disruption of the peroxisome proliferator-activated receptor ␥ (PPAR␥) gene causes embryonic lethality due to placental dysfunction. To circumvent this, a PPAR␥ conditional gene knockout mouse was produced by using the Cre-loxP system. The targeted allele, containing loxP sites flanking exon 2 of the PPAR␥ gene, was crossed into a transgenic mouse line expressing Cre recombinase under the control of the alpha/beta interferon-inducible (MX) promoter. Induction of the MX promoter by pIpC resulted in nearly complete deletion of the targeted exon, a corresponding loss of full-length PPAR␥ mRNA transcript and protein, and marked reductions in basal and troglitazone-stimulated expression of the genes encoding lipoprotein lipase, CD36, LXR␣, and ABCG1 in thioglycolate-elicited peritoneal macrophages. Reductions in the basal levels of apolipoprotein E (apoE) mRNA in macrophages and apoE protein in total plasma and high-density lipoprotein (HDL) were also observed in pIpC-treated PPAR␥-MXCre ؉ mice. Basal cholesterol efflux from cholesterolloaded macrophages to HDL was significantly reduced after disruption of the PPAR␥ gene. Troglitazone selectively inhibited ABCA1 expression (while rosiglitazone, ciglitazone, and pioglitazone had little effect) and cholesterol efflux in both PPAR␥-deficient and control macrophages, indicating that this drug can exert paradoxical effects on cholesterol homeostasis that are independent of PPAR␥. Together, these data indicate that PPAR␥ plays a critical role in the regulation of cholesterol homeostasis by controlling the expression of a network of genes that mediate cholesterol efflux from cells and its transport in plasma.Peroxisome proliferator-activated receptor ␥ (PPAR␥) is a member of the nuclear receptor superfamily that has been implicated to play a possible role in adipocyte differentiation (34,73,82), insulin sensitization (42, 51, 61), and tumor suppression (11,14,25,37,43,57,77,88). Ligands for PPAR␥ include modified fatty acids, members of the prostanoid family, linoleic acid derivatives (38,39,58), and synthetic insulinsensitizing thiazolidinedione compounds (TZDs) such as BRL-49653 (rosiglitazone), pioglitazone, and troglitazone (28,29,38,39,58).PPAR␥ is abundantly expressed in adipose tissue and at lower levels in T cells, neutrophils, epithelial cells, smooth muscle cells, and macrophages (19,48,81). The discovery of high levels of PPAR␥ protein expression in the foam cells of atherosclerotic lesions (53, 71) has led to intensive research efforts to identify possible roles of PPAR␥ in regulating cholesterol flux in macrophages and to better understand the possible effects of TZDs on the development of atherosclerosis. With regard to cholesterol uptake, the scavenger receptor, CD36, was demonstrated to be a direct target gene of PPAR␥ in macrophages (15,56,58,87). Recent studies have shown, however, that neither treatment of macrophages with TZDs (56) nor mutation of the PPAR␥ gene (15) significantly alters oxLDL uptake. Likewise, the basal expression of other scavenger rec...

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