scholarly journals Design and synthesis of fused soluble epoxide hydrolase/peroxisome proliferator-activated receptor modulators

MedChemComm ◽  
2016 ◽  
Vol 7 (6) ◽  
pp. 1209-1216 ◽  
Author(s):  
R. Blöcher ◽  
C. Lamers ◽  
S. K. Wittmann ◽  
O. Diehl ◽  
T. Hanke ◽  
...  
Keyword(s):  
Type Ii Diabetes ◽  
Epoxide Hydrolase ◽  
Complex Disease ◽  
Soluble Epoxide Hydrolase ◽  
Peroxisome Proliferator ◽  
Type Ii ◽  
Peroxisome Proliferator Activated Receptor ◽  
Design And Synthesis ◽  
Disease Cluster ◽  
Receptor Modulators

Metabolic syndrome (MetS) is a widespread, complex disease cluster which consists of hypertension, atherosclerosis, dyslipidaemia and type II diabetes.

scholarly journals Deletion of soluble epoxide hydrolase enhances coronary reactive hyperemia in isolated mouse heart: role of oxylipins and PPARγ

2016 ◽  
Vol 311 (4) ◽  
pp. R676-R688 ◽  
Author(s):  
Ahmad Hanif ◽  
Matthew L. Edin ◽  
Darryl C. Zeldin ◽  
Christophe Morisseau ◽  
Mohammed A. Nayeem
Keyword(s):  
Epoxide Hydrolase ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Reactive Hyperemia ◽  
Soluble Epoxide Hydrolase ◽  
Mouse Heart ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist

The relationship between soluble epoxide hydrolase (sEH) and coronary reactive hyperemia (CRH) response to a brief ischemic insult is not known. Epoxyeicosatrienoic acids (EETs) exert cardioprotective effects in ischemia/reperfusion injury. sEH converts EETs into dihydroxyeicosatrienoic-acids (DHETs). Therefore, we hypothesized that knocking out sEH enhances CRH through modulation of oxylipin profiles, including an increase in EET/DHET ratio. Compared with sEH+/+, sEH−/− mice showed enhanced CRH, including greater repayment volume (RV; 28% higher, P < 0.001) and repayment/debt ratio (32% higher, P < 0.001). Oxylipins from the heart perfusates were analyzed by LC-MS/MS. The 14,15-EET/14,15-DHET ratio was 3.7-fold higher at baseline ( P < 0.001) and 5.6-fold higher post-ischemia ( P < 0.001) in sEH−/− compared with sEH+/+ mice. Likewise, the baseline 9,10- and 12,13-EpOME/DiHOME ratios were 3.2-fold ( P < 0.01) and 3.7-fold ( P < 0.001) higher, respectively in sEH−/− compared with sEH+/+ mice. 13-HODE was also significantly increased at baseline by 71% ( P < 0.01) in sEH−/− vs. sEH+/+ mice. Levels of 5-, 11-, 12-, and 15-hydroxyeicosatetraenoic acids were not significantly different between the two strains ( P > 0.05), but were decreased postischemia in both groups ( P = 0.02, P = 0.04, P = 0.05, P = 0.03, respectively). Modulation of CRH by peroxisome proliferator-activated receptor gamma (PPARγ) was demonstrated using a PPARγ-antagonist (T0070907), which reduced repayment volume by 25% in sEH+/+ ( P < 0.001) and 33% in sEH−/− mice ( P < 0.01), and a PPARγ-agonist (rosiglitazone), which increased repayment volume by 37% in both sEH+/+ ( P = 0.04) and sEH−/− mice ( P = 0.04). l-NAME attenuated CRH in both sEH−/− and sEH+/+. These data demonstrate that genetic deletion of sEH resulted in an altered oxylipin profile, which may have led to an enhanced CRH response.

scholarly journals Inhibition of soluble epoxide hydrolase ameliorates hyperhomocysteinemia-induced hepatic steatosis by enhancing β-oxidation of fatty acid in mice

2019 ◽  
Vol 316 (4) ◽  
pp. G527-G538 ◽  
Author(s):  
Liu Yao ◽  
Boyang Cao ◽  
Qian Cheng ◽  
Wenbin Cai ◽  
Chenji Ye ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nonalcoholic Fatty Liver

Hepatic steatosis is the beginning phase of nonalcoholic fatty liver disease, and hyperhomocysteinemia (HHcy) is a significant risk factor. Soluble epoxide hydrolase (sEH) hydrolyzes epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids, attenuating their cardiovascular protective effects. However, the involvement of sEH in HHcy-induced hepatic steatosis is unknown. The current study aimed to explore the role of sEH in HHcy-induced lipid disorder. We fed 6-wk-old male mice a chow diet or 2% (wt/wt) high-metnionine diet for 8 wk to establish the HHcy model. A high level of homocysteine induced lipid accumulation in vivo and in vitro, which was concomitant with the increased activity and expression of sEH. Treatment with a highly selective specific sEH inhibitor (0.8 mg·kg−1·day−1 for the animal model and 1 μM for cells) prevented HHcy-induced lipid accumulation in vivo and in vitro. Inhibition of sEH activated the peroxisome proliferator-activated receptor-α (PPAR-α), as evidenced by elevated β-oxidation of fatty acids and the expression of PPAR-α target genes in HHcy-induced hepatic steatosis. In primary cultured hepatocytes, the effect of sEH inhibition on PPAR-α activation was further confirmed by a marked increase in PPAR-response element luciferase activity, which was reversed by knock down of PPAR-α. Of note, 11,12-EET ligand dependently activated PPAR-α. Thus increased sEH activity is a key determinant in the pathogenesis of HHcy-induced hepatic steatosis, and sEH inhibition could be an effective treatment for HHcy-induced hepatic steatosis. NEW & NOTEWORTHY In the current study, we demonstrated that upregulation of soluble epoxide hydrolase (sEH) is involved in the hyperhomocysteinemia (HHcy)-caused hepatic steatosis in an HHcy mouse model and in murine primary hepatocytes. Improving hepatic steatosis in HHcy mice by pharmacological inhibition of sEH to activate peroxisome proliferator-activated receptor-α was ligand dependent, and sEH could be a potential therapeutic target for the treatment of nonalcoholic fatty liver disease.

Design and Synthesis of Dual Modulators of Soluble Epoxide Hydrolase and Peroxisome Proliferator-Activated Receptors

2012 ◽  
Vol 55 (23) ◽  
pp. 10771-10775 ◽  
Author(s):  
Estel.la Buscató ◽  
René Blöcher ◽  
Christina Lamers ◽  
Franca-Maria Klingler ◽  
Steffen Hahn ◽  
...  
Keyword(s):  
Epoxide Hydrolase ◽  
Soluble Epoxide Hydrolase ◽  
Peroxisome Proliferator ◽  
Design And Synthesis ◽  
Peroxisome Proliferator Activated Receptors

scholarly journals Troglitazone Effects on Gene Expression in Human Skeletal Muscle of Type II Diabetes Involve Up-Regulation of Peroxisome Proliferator-Activated Receptor-γ1

1998 ◽  
Vol 83 (8) ◽  
pp. 2830-2835 ◽  
Author(s):  
Kyong Soo Park ◽  
Theodore P. Ciaraldi ◽  
Kristin Lindgren ◽  
Leslie Abrams-Carter ◽  
Sunder Mudaliar ◽  
...  
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Type Ii Diabetes ◽  
Insulin Action ◽  
Peroxisome Proliferator ◽  
Type Ii ◽  
Peroxisome Proliferator Activated Receptor ◽  
Nondiabetic Control ◽  
Muscle Cultures ◽  
Stimulation Of

abstract Troglitazone, besides improving insulin action in insulin-resistant subjects, is also a specific ligand for the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ). To determine whether troglitazone might enhance insulin action by stimulation of PPARγ gene expression in muscle, total PPARγ messenger RNA (mRNA), and protein were determined in skeletal muscle cultures from nondiabetic control and type II diabetic subjects before and after treatment of cultures with troglitazone (4 days ± troglitazone, 11.5μ m). Troglitazone treatment increased PPARγ mRNA levels up to 3-fold in muscle cultures from type II diabetics (277 ± 63 to 630 ± 100 × 103 copies/μg total RNA, P = 0.003) and in nondiabetic control subjects (200 ± 42 to 490 ± 81, P = 0.003). PPARγ protein levels in both diabetic (4.7 ± 1.6 to 13.6± 3.0 AU/10 μg protein, P &lt; 0.02) and nondiabetic cells (7.4 ± 1.0 to 12.7 ± 1.8, P &lt; 0.05) were also up-regulated by troglitazone treatment. Increased PPARγ was associated with stimulation of human adipocyte lipid binding protein (ALBP) and muscle fatty acid binding protein (mFABP) mRNA, without change in the mRNA for glycerol-3-phosphate dehydrogenase, PPARδ, myogenin, uncoupling protein-2, or sarcomeric α-actin protein. In summary, we showed that troglitazone markedly induces PPARγ, ALBP, and mFABP mRNA abundance in muscle cultures from both nondiabetic and type II diabetic subjects. Increased expression of PPARγ protein and other genes involved in glucose and lipid metabolism in skeletal muscle may account, in part, for the insulin sensitizing effects of troglitazone in type II diabetes.

Action of epoxyeicosatrienoic acids on cellular function

2007 ◽  
Vol 292 (3) ◽  
pp. C996-C1012 ◽  
Author(s):  
Arthur A. Spector ◽  
Andrew W. Norris
Keyword(s):  
Epoxide Hydrolase ◽  
Direct Interaction ◽  
Soluble Epoxide Hydrolase ◽  
Epoxyeicosatrienoic Acids ◽  
Peroxisome Proliferator ◽  
Potential Therapeutic Target ◽  
Peroxisome Proliferator Activated Receptor ◽  
Effector System ◽  
Modulation Of Gene Expression ◽  
Cytochrome P 450

Epoxyeicosatrienoic acids (EETs), which function primarily as autocrine and paracrine mediators in the cardiovascular and renal systems, are synthesized from arachidonic acid by cytochrome P-450 epoxygenases. They activate smooth muscle large-conductance Ca2+-activated K+ channels, producing hyperpolarization and vasorelaxation. EETs also have anti-inflammatory effects in the vasculature and kidney, stimulate angiogenesis, and have mitogenic effects in the kidney. Many of the functional effects of EETs occur through activation of signal transduction pathways and modulation of gene expression, events probably initiated by binding to a putative cell surface EET receptor. However, EETs are rapidly taken up by cells and are incorporated into and released from phospholipids, suggesting that some functional effects may occur through a direct interaction between the EET and an intracellular effector system. In this regard, EETs and several of their metabolites activate peroxisome proliferator-activated receptor α (PPARα) and PPARγ, suggesting that some functional effects may result from PPAR activation. EETs are metabolized primarily by conversion to dihydroxyeicosatrienoic acids (DHETs), a reaction catalyzed by soluble epoxide hydrolase (sEH). Many potentially beneficial actions of EETs are attenuated upon conversion to DHETs, which do not appear to be essential under routine conditions. Therefore, sEH is considered a potential therapeutic target for enhancing the beneficial functions of EETs.

Sign in / Sign up

Export Citation Format

Share Document