Linking Induction and Transrepression of PPARβ/δ with Cellular Function

The copyrights of all papers published in this journal are retained by the respective authors as per the 'Creative Commons Attribution License' (http://creativecommons.org/licenses/by/3.0/).Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear hormone receptor superfamily. PPARβ/δ is ubiquitously expressed and has a central role in homeostasis, and has been suggested as a therapeutic target for a number of metabolic and cardiovascular disorders. This important nuclear receptor controls transcription under different modes of molecular activity which directly control the cellular function and fate of tissues. This complex activity of induction and transrepression of gene expression (with and without exogenous ligands) is poorly understood and yet understanding this molecular control through novel drug development would led to control over a key molecular switch in all cells. This review outlines the main molecular mechanisms of PPARβ/δ, and links the modes of activity to the signalling pathways in inflammation, proliferation and senescence, with the goal to understand how this will translate into novel drug design to control the PPARβ/δ molecular switch.Peer reviewe

Tertiary alkylamines as nucleophiles in substitution reactions at heteroaromatic halide during the synthesis of the highly potent pirinixic acid derivative 2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid (YS-121)

YS-121 [2-(4-chloro-6-(2,3-dimethylphenylamino)pyrimidin-2-ylthio)octanoic acid] is the result of target-oriented structural derivatization of pirinixic acid. It is a potent dual PPARα/γ-agonist, as well as a potent dual 5-LO/mPGES-1-inhibitor. Additionally, recent studies showed an anti-inflammatory efficacy in vivo. Because of its interference with many targets, YS-121 is a promising drug candidate for the treatment of inflammatory diseases. Ongoing preclinical studies will thus necessitate huge amounts of YS-121. To cope with those requirements, we have optimized the synthesis of YS-121. Surprisingly, we isolated and characterized byproducts during the resulting from nucleophilic aromatic substitution reactions by different tertiary alkylamines at a heteroaromatic halide. These amines should actually serve as assisting bases, because of their low nucleophilicity. This astonishing fact was not described in former publications concerning that type of reaction and, therefore, might be useful for further reaction improvement in general. Furthermore, we could develop a proposal for the mechanism of that byproduct formation

Relationship between PPARα activation and NO on proximal tubular Na(+ )transport in the rat

BACKGROUND: Nitric oxide (NO) regulates renal proximal tubular (PT) Na(+ )handling through modulation of Na(+)-K(+ )ATPase. Peroxisome Proliferator Activated Receptorα (PPARα), a nuclear transcription factor, is expressed in PTs and has been reported to influence NO generation/activity in renal tissues. This study tested the hypothesis that PPARα interacts with NO and thereby affects renal tubular Na(+ )transport. Urinary excretion of nitrite (UNO(X)V) and Na(+ )(U(Na)V) and PT Na(+ )transport (Na(+)-K(+ )ATPase activity) were determined in rats treated with clofibrate (250 mg/kg i.p) or WY14643 (45 mg/kg; i.p.), a PPARα ligand, 2% NaCl (orally), clofibrate/NaCl, L-NAME, an inhibitor of NO production (100 mg/kg; orally), L-NAME/Clofibrate. RESULTS: Clofibrate or WY14643 increased PPARα expression by 106 ± 7% (p < 0.05) and 113 ± 8% (p < 0.05), respectively. Similarly, clofibrate and WY14643 increased expression of MCAD, a downstream target protein of PPARα by 123 ± 8% (p < 0.05) and 143 ± 8% (p < 0.05), respectively. L-NAME attenuated clofibrate-induced increase in PPARα expression by 27 ± 2% (p < 0.05) but did not affect MCAD expression. UNO(X)V excretion increased 3–4 fold in rats treated with clofibrate, WY14643 or NaCl from 44 ± 7 to 170 ± 15, 144 ± 18 or 132 ± 11 nmol/24 hr, respectively (p < 0.05). Similarly, clofibrate, WY14643 or NaCl elicited a 2–5 fold increase in U(Na)V. L-NAME significantly reduced basal UNO(X)V and U(Na)V and abolished the clofibrate-induced increase. Clofibrate, WY14643, NaCl or clofibrate + NaCl treatment reduced Na(+)-K(+)-ATPase activity in the PT by 89 ± 23, 62 ± 10, 43 ± 9 and 82 ± 15% (p < 0.05), respectively. On the contrary, L-NAME or ODQ, inhibitor of sGC, abolished the inhibition of Na(+)-K(+)-ATPase activity by clofibrate (p < 0.05). Clofibrate either alone or with NaCl elicited ~2-fold increase in the expression of the α1 subunit of Na(+)-K(+ )ATPase in the PT while L-NAME abolished clofibrate-induced increase in Na(+)-K(+ )ATPase expression. CONCLUSION: These data suggest that PPARα activation, through increased NO generation promotes renal excretion of Na(+ )through reduced Na(+)-K(+ )ATPase activity in the PT probably via post translational modification of Na(+)-K(+)-ATPase

The role of peroxisome proliferator activated-receptor gamma in ovarian function

The transcription factor, peroxisome proliferator activated-receptor γ (PPARγ), regulates many processes critical for normal ovarian function. The role of PPARγ in the ovary was investigated by determining its expression throughout the bovine estrous cycle, and luteal tissue was cultured with agonists and an antagonist of PPARγ to determine its impact on progesterone production. Protein, but not mRNA for PPARγ, was lower in regressing compared to functional luteal tissue. Treatment with a PPARγ agonist decreased progesterone secretion from late phase luteal tissue. These findings indicate that PPARγ may play a role in luteal formation/function, and alter progesterone production during specific stages of the ovarian cycle. To facilitate further study of how PPARγ impacts ovarian biology, transgenic mice were developed with the gene for PPARγ specifically disrupted in granulosa cells. Knowing what genes are regulated by PPARγ in the ovary will aid in understanding the mechanisms behind the cyclic pattern of gene expression driving normal ovarian function