Overlapping Transcriptional Programs Regulated by the Nuclear Receptors Peroxisome Proliferator-Activated Receptor α, Retinoid X Receptor, and Liver X Receptor in Mouse Liver

Abstract

Lipid homeostasis is controlled in part by the nuclear receptors peroxisome proliferator (PP)-activated receptor ␣ (PPAR␣) and liver X receptor (LXR) through regulation of genes involved in fatty acid and cholesterol metabolism. Exposure to agonists of retinoid X receptor (RXR), the obligate heterodimer partner of PPAR␣, and LXR results in responses that partially overlap with those of PP. To better understand the gene networks regulated by these nuclear receptors, transcript profiles were generated from the livers of wild-type and PPAR␣-null mice exposed to the RXR pan-agonist 3,7-dimethyl-6S,7S-methano, 7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]-2E,4E-heptadienoic acid (AGN194,204) or the PPAR pan-agonist WY-14,643 (WY; pirinixic acid) and compared with the profiles from the livers of wild-type and LXR␣/LXR␤-null mice after exposure to the LXR agonist N- (2,2,2-trifluoroethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)phenyl] sulfonamide (T0901317). All 218 WY-regulated genes altered in wild-type mice required PPAR␣. Remarkably, ϳ80% of genes regulated by AGN194,204 required PPAR␣ including cell-cycle genes, consistent with AGN-induced hepatocyte proliferation having both PPAR␣-dependent and -independent components. Overlaps of ϳ31 to 62% in the transcript profiles of WY, AGN194,204, and T0901317 required PPAR␣ and LXR␣/LXR␤ for statistical significance. Ofthe 50 overlapping genes regulated by T0901317 and WY, all but one were regulated in a similar direction. These results 1) identify new transcriptional targets of PPAR␣ and RXR important in regulating lipid metabolism and liver homeostasis, 2) illustrate the importance of PPAR␣ in regulation of gene expression by a prototypical PP and by an RXR agonist, and 3) provide support for an axis of PPAR␣-RXR-LXR in which agonists for each nuclear receptor regulate an overlapping set of genes in the mouse liver.

Time course investigation of PPARα- and Kupffer cell-dependent effects of WY-14,643 in mouse liver using microarray gene expression

“…This effect was most pronounced at 1 and 4 weeks after treatment, but the earliest onset may occur as early as 24 hrs post-dosing ( Figure 3). Decrease in complement activation system was associated with reduced transcript levels of complements 1 (C1), C2, C5, C8, C9 and serine protease mannan-binding lectin serine peptidase (Masp1), effects similar to those reported by others (Wong and Gill, 2002;Anderson et al, 2004a;Currie et al, 2005). In addition to serving as important mediators of innate and adaptive immune response, complements play a major role in cell death byopsonizing apoptotic cells which are later cleared by phagocytes (Fishelson et al, 2001;Flierman and Daha, 2007).…”

“…While the initial timing of most profound effects on gene expression varied among groups, a uniformly robust response was observed in both wild type strains and p47 phox -null mice with 1 or 4 wk of continued WY-14,643 treatment. The large majority of the changes were PPARα-dependent with few genes being affected by WY-14,643 in Pparα-null mice (see below), a response that has been demonstrated in other gene array studies (Anderson et al, 2004a;Anderson et al, 2004b). Pathway analysis of the significantly different genes identified a number of biological processes that were perturbed by peroxisome proliferators in a doseand time-dependent manner (Figure 3).…”

Gene Profiling in the Livers of Wild-type and PPARα-Null Mice Exposed to Perfluorooctanoic Acid

“…This dosing paradigm was based on published data and represented conditions in which steady-state serum levels would be achieved for PFOA (Lau et al, 2006). The dose level for Wy14,643 was also based on previously published data (Anderson et al, 2004). With the exception of hepatomegaly, these doses were below those required to induce acute toxicity.…”

Multiple facets of membrane lipids and the diversity of their action mode with special emphasis on the central nervous system

“…The authors have particularly studied the coupling between the activation of phospholipases and the retinoic acid receptor-mediated gene transcription. The retinoic acid receptor pathway is known to activate genes involved in lipid metabolism [12] and to stimulate morphological differentiation of neuronal cells [13]. Their striking conclusion is that retinoic acid increases the transcription and thus the activity of nuclear phospholipases, resulting in the hydrolysis of nuclear phospholipids without an effect on non-nuclear membranes.…”