The peroxisome proliferator-activated receptor δ, an integrator of transcriptional repression and nuclear receptor signaling

Abstract

The three PPAR (peroxisome proliferator-activated receptor) isoforms are critical regulators of lipid homeostasis by controlling the balance between the burning and storage of long chain fatty acids. Whereas PPAR␣ and PPAR␥ have been studied extensively, the function of PPAR␦ remains the most elusive. Intriguingly, in cotransfection experiments, PPAR␦ is a potent inhibitor of ligandinduced transcriptional activity of PPAR␣ and PPAR␥. This inhibition is achieved, in part, by binding of PPAR␦ to a peroxisome proliferator response element and the association of nonliganded PPAR␦ with corepressors SMRT (silencing mediator for retinoid and thyroid hormone receptors), SHARP (SMRT and histone deacetylase-associated repressor protein), and class I histone deacetylases. Stable expression of PPAR␦ inhibits the expression of endogenous PPAR␣ target gene expression in 3T3-PPAR␣ cells, whereas a PPAR␦ mutant that does not interact with the corepressor SMRT loses its ability to repress the induction of PPAR␣ target gene. Similarly, stable expression of PPAR␦ in 3T3-PPAR␥ cells leads to inhibition of PPAR␥ target gene expression and PPAR␥-mediated adipogenesis. Given the widespread expression of PPAR␦ and the restricted pattern for PPAR␣ and PPAR␥, these results suggest a role for PPAR␦ as a gateway receptor whose relative levels of expression can be used to modulate PPAR␣ and PPAR␥ activity.T he PPAR subfamily includes three isoforms (␣, ␥, and ␦) that all bind to the peroxisome proliferator response elements (PPRE) as a heterodimer with retinoid X receptor (RXR), yet exhibit distinct tissue distribution and physiological function. PPAR␣ is highly expressed in the liver and was originally identified as a molecule that mediates the transcriptional effects of drugs that induce peroxisome proliferation in rodents (1). In addition to its activation in response to peroxisome proliferators such as Wy14,643, PPAR␣ is also activated by a variety of medium-and long-chain fatty acids (2) and has been shown to stimulate lipid metabolism by the induction of peroxisomal ␤-oxidation and fatty acid -hydroxylation (3). Mice lacking functional PPAR␣ are incapable of responding to peroxisome proliferators and fail to induce expression of a variety of genes required for the metabolism of fatty acids, including acyl-CoA oxidase (AOX) (4).PPAR␥ is highly enriched in adipose tissue and has been shown to play a central role in activating adipogenesis both in vitro and in vivo (5, 6). It is also expressed at high levels in lipid-accumulating macrophages and plays a role in the development of the atherogenic lesion (7). PPAR␥ has been shown to be activated by 15-deoxy-(12,14)-prostaglandin J2 (15d-PGJ2) or its synthetic analog thiazolidinedione, a novel class of antidiabetic drugs (8, 9). The PPAR␥-null mice are embryonic lethal due in part to disrupted placental function (6). Rescue of the placental defect results in lipid dystrophy and neonatal death (10,11).PPAR␦ (also known as PPAR␤) is widely expressed with relatively higher levels in brain, col...

Gemfibrozil, a Lipid-lowering Drug, Increases Myelin Genes in Human Oligodendrocytes via Peroxisome Proliferator-activated Receptor-β

“…Taken together, these results indicate that gemfibrozil stimulates the expression of myelin genes via PPAR-␤ but not via either PPAR-␣ or PPAR-␥. Our results are consistent with published reports that demonstrate reduced myelination of the corpus callosum in PPAR-␤-null mice and suggest a role of PPAR-␤ in oligodendroglial lipid metabolism and myelinogenesis (41,42).…”

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

“…Although not examined in the current study, there is evidence that PPAR␤/␦ can also modulate gene expression by repressing transcription. 48 Thus, it remains possible that PPAR␤/␦ protects against liver toxicity by repressing expression of TWEAK receptor, which in turn reduces NF-B activity. Collectively, results from the current present studies suggest that PPAR␤/␦ could protect against liver toxicity by directly interacting with NF-B or by repressing TWEAK receptor expression.…”

Metabolism and Functions of Lipids and Fatty Acids in Teleost Fish

“…However, in salmon at least, it appears that there are multiple genes for PPARβ isoforms (Leaver, personal communication) and since there is only one PPARβ gene in mammals, there yet may be some divergence in the functions of PPARs between fish and mammals. Interestingly, although PPARβ is probably the least well studied PPAR isoform, it has recently been shown that PPARβ may function as a negative regulator of PPARα and PPARγ function by competing for binding at gene regulatory elements and then recruiting proteins involved in depressing transcriptional activity (Shi et al, 2002). (Kawashima et al, 1990;Gronn et al, 1992;Alegret et al, 1995) and clofibrate has been shown to increase the desaturation of 20:5n-3 in rainbow trout (Tocher and Sargent, 1993).…”