Differential Activation of Peroxisome Proliferator-activated Receptors by Eicosanoids

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that regulate gene transcription in response to peroxisome proliferators and fatty acids. PPARs also play an important role in the regulation of adipocyte differentiation. It is unclear, however, what naturally occurring compounds activate each of the PPAR subtypes. To address this issue, a screening assay was established using heterologous fusions of the bacterial tetracycline repressor to several members of the peroxisome proliferator-activated receptor (PPAR) family. This assay was employed to compare the activation of PPAR family members by known PPAR activators including peroxisome proliferators and fatty acids. Interestingly, the activation of PPARs by fatty acids was partially inhibited by the cyclooxygenase inhibitor indomethacin, which prevents prostaglandin synthesis. Indeed, prostaglandins PGA1 and 2, PGD1 and 2, and PGJ2-activated PPARs, while a number of other prostaglandins had no effect. We also screened a variety of hydroxyeicosatetraenoic acids (HETEs) for the ability to activate PPARs. 8(S)-HETE, but not other (S)-HETEs, was a strong activator of PPAR␣. Remarkably, PPAR activation by 8(S)-HETE was stereoselective. In addition, 8(S)-HETE was able to induce differentiation of 3T3-L1 preadipocytes. These results indicate that PPARs are differentially activated by naturally occurring eicosanoids and related molecules.The cloning and characterization of nuclear receptors has greatly enhanced our understanding of gene regulation by lipophilic hormones such as steroids, vitamin D, thyroxine, and retinoids. These receptors comprise a superfamily of transcription factors containing highly related DNA-binding domains (1, 2). This family includes multiple subtypes of receptors for thyroxine and retinoids, encoded by distinct genes which are regulated quite differently during development and in the adult.

Effects of arachidonic acid on the concentration of hydroxyeicosatetraenoic acids in culture media of mesenchymal stromal cells differentiating into adipocytes or osteoblasts

“…This suggests that such HETE may be a mediator of the adipogenesis activation in our experimental model. This is in agreement with the fact that 8-HETE is a PPARa activator, and it can induce the 3T3-L1 pre-adipocyte differentiation toward adipocytes (Yu et al 1995). The studied HETE in cells induced to differentiate into osteoblasts were present at higher concentrations than in adipogenic media, in general.…”

“…LOX acts on liberated free AA to generate hydroperoxyeicosatetraenoic acids, which are unstable intermediates, being further either hydrolyzed into hydroxyeicosatetraenoic acids (HETE) via lipoxygenase catalysis or by non-enzymatic oxidative reactions (Niki et al 2005), or enzymatically converted into leukotrienes such as 5(6)-epoxy(oxido)eicosatetraenoic acid (leukotriene A4; LTA4) and lipoxins, which may be involved in important physiological events such as inflammation (Wahli and Michalik 2012). On the other hand, the HETE are PPARc agonists and may influence cellular differentiation (Ban et al 2011;Yu et al 1995). Additionally, LTA4 may be further converted into either dihydroxyeicosatetraenoic acid (LTB4) by an epoxide hydrolase or hydroxy-glutathionyleicosatetraenoic acid (LTC4) by a glutathione transferase (Needleman et al 1986).…”

The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator-activated receptor-β/δ (PPARβ/δ)

“…PPARβ/δ agonists include linoleic acid, oleic acid, arachidonic acid and EPA, which has been co-crystallized within the ligand binding domain of this nuclear receptor [25]. Prostaglandin A1 (PGA1), PGD2 and PGD1 can activate PPARβ/δ in reporter assays [27]. Similar to PPARα and γ, incubation of triglyceride rich lipoproteins with LPL results in the production of PPARβ ligands [28,29].…”

Multiplication and death-type of leukemia cell lines exposed to very long-chain polyunsaturated fatty acids

“…40,41 Another molecular mechanism for the action of PUFA on cell death may be transmitted via PPAR receptors acting as transcription factors in combination with fatty acids. [42][43][44][45][46] Three human PPAR receptors (␣, ␦ and ␥) have been identified, and mRNA analyses demonstrated that all three receptors were expressed in U-698, Raji and Ramos cells (Finstad et al unpublished data). A possible mechanism whereby activation of PPAR receptors may induce apoptosis, may be via antagonizing the activity AP-1, NF-B and STAT, 47 as these transcription factors may influence the cellular suicide program.…”