Inhibition of peroxisome-proliferator-activated receptor (PPAR)α by MK886

Kehrer, James P.; Biswal, Shyam; La, Eunhye; Thuillier, Philippe; Datta, Kaushik; Fischer, Susan M.; Heuvel, John P. Vanden

doi:10.1042/0264-6021:3560899

Cited by 127 publications

(114 citation statements)

References 46 publications

(67 reference statements)

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“…To confirm the involvement of a fenofibrate target molecule, PPAR-␣, in simvastatin actions, we used siRNA against PPAR-␣ and MK886, a PPAR-␣ inhibitor (33). SiRNA against PPAR-␣ inhibited the enhancement of SR-BI expression induced by simvastatin as well as fenofibrate (Fig.…”

Section: Involvement Of Ppar-␣ In Simvastatin Actionsmentioning

confidence: 99%

Induction of Scavenger Receptor Class B Type I Is Critical for Simvastatin Enhancement of High-Density Lipoprotein-Induced Anti-Inflammatory Actions in Endothelial Cells

Kimura

Mogi

Tomura

et al. 2008

The Journal of Immunology

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Changes in plasma lipoprotein profiles, especially low levels of high-density lipoprotein (HDL), are a common biomarker for several inflammatory and immune diseases, including atherosclerosis and rheumatoid arthritis. We examined the effect of simvastatin on HDL-induced anti-inflammatory actions. HDL and sphingosine 1-phosphate (S1P), a bioactive lipid component of the lipoprotein, inhibited TNF α-induced expression of VCAM-1, which was associated with NO synthase (NOS) activation, in human umbilical venous endothelial cells. The HDL- but not S1P-induced anti-inflammatory actions were enhanced by a prior treatment of the cells with simvastatin in a manner sensitive to mevalonic acid. Simvastatin stimulated the expression of scavenger receptor class B type I (SR-BI) and endothelial NOS. As for S1P receptors, however, the statin inhibited the expression of S1P3 receptor mRNA but caused no detectable change in S1P1 receptor expression. The reconstituted HDL, a stimulator of SR-BI, mimicked HDL actions in a simvastatin-sensitive manner. The HDL- and reconstituted HDL-induced actions were blocked by small interfering RNA specific to SR-BI regardless of simvastatin treatment. The statin-induced expression of SR-BI was attenuated by constitutively active RhoA and small interfering RNA specific to peroxisome proliferator-activated receptor-α. Administration of simvastatin in vivo stimulated endothelial SR-BI expression, which was accompanied by the inhibition of the ex vivo monocyte adhesion in aortas from TNF α-injected mice. In conclusion, simvastatin induces endothelial SR-BI expression through a RhoA- and peroxisome proliferator-activated receptor-α-dependent mechanism, thereby enhancing the HDL-induced activation of NOS and the inhibition of adhesion molecule expression.

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Section: Involvement Of Ppar-␣ In Simvastatin Actionsmentioning

confidence: 99%

Induction of Scavenger Receptor Class B Type I Is Critical for Simvastatin Enhancement of High-Density Lipoprotein-Induced Anti-Inflammatory Actions in Endothelial Cells

Kimura

Mogi

Tomura

et al. 2008

The Journal of Immunology

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“…To test the role of PPAR-␣ in the induction of TRB3 expression, primary cultured hepatocytes were pretreated with an inhibitor of PPAR-␣, MK886. 35 As shown in Figure 6, A and B, MK886 (50 mol/L) significantly inhibited the expression of TRB3 induced by homocysteine. In addition, we disrupted endogenous PPAR-␣ expression in primary cultured hepatocytes by siRNA (see Supplemental Figure S3 at http://ajp.amjpathol.org).…”

Section: Induction Of Trb3 Expression In Hhcy Mice Is Mediated By Thementioning

confidence: 99%

Inhibition of Hepatic Glycogen Synthesis by Hyperhomocysteinemia Mediated by TRB3

Liu

et al. 2011

The American Journal of Pathology

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Recently, epidemiological and experimental studies have linked hyperhomocysteinemia (HHcy) to insulin resistance. However, whether HHcy impairs glucose homeostasis by affecting glycogenesis in the liver is not clear. In the present study, we investigated the effect of HHcy on hepatic glycogen synthesis. Hyperhomocysteinemia was induced in mice by drinking water containing two percent methionine. Mice with HHcy showed an increase in the phosphorylation of glycogen synthase and a significant decrease in hepatic glycogen content and the rate of glycogen synthesis. The expression of TRB3 (tribbles-related protein 3) was up-regulated in the liver of mice with HHcy, concomitantly with the dephosphorylation of glycogen synthase kinase-3␤ and Akt. The knockdown of TRB3 by short hairpin RNA suppressed the dephosphorylation of these two kinases. Homocysteine induced an increase in the levels of hepatic cAMP and cAMP response element-binding protein phosphorylation, which in turn up-regulated the expression of peroxisome proliferator-activated receptor (PPAR)-␥ coactivator-1␣ and TRB3. The inhibition of PPAR-␣ by its inhibitor, MK886, or knockdown of PPAR-␣ by small interfering RNA significantly inhibited the expression of TRB3 induced by homocysteine. The current study demonstrates that HHcy impairs hepatic glycogen synthesis by inducing the expression of TRB3. These results provide a novel explanation for the development and progression of insulin resistance in HHcy.

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“…Octanoyl-CoA dehydrogenase activity in patient cells was higher than that in control cells, and this increased activity was reduced by treatment with MK886, a PPARα-specific antagonist (Kehrer et al 2001) (Fig. 3C).…”

Section: Octanoyl-coa Dehydrogenase Activitymentioning

confidence: 99%

“…MK886, a PPARα-specific antagonist (Kehrer et al 2001), and fenofibrate (FF) were obtained from Wako Pure Chemical (Osaka, Japan) and Sigma Chemical Company (St. Louis, MO, USA), respectively.…”

Section: Chemicalsmentioning

confidence: 99%

Activation of PPAR<i>α</i> by Fatty Acid Accumulation Enhances Fatty Acid Degradation and Sulfatide Synthesis

Yang

Feng

Zhang

et al. 2016

Tohoku J. Exp. Med.

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Very-long-chain acyl-CoA dehydrogenase (VLCAD) catalyzes the first reaction in the mitochondrial fatty acid β-oxidation pathway. VLCAD deficiency is associated with the accumulation of fat in multiple organs and tissues, which results in specific clinical features including cardiomyopathy, cardiomegaly, muscle weakness, and hepatic dysfunction in infants. We speculated that the abnormal fatty acid metabolism in VLCAD-deficient individuals might cause cell necrosis by fatty acid toxicity. The accumulation of fatty acids may activate peroxisome proliferator-activated receptor (PPAR), a master regulator of fatty acid metabolism and a potent nuclear receptor for free fatty acids. We examined six skin fibroblast lines, derived from VLCAD-deficient patients and identified fatty acid accumulation and PPARα activation in these cell lines. We then found that the expression levels of three enzymes involved in fatty acid degradation, including long-chain acyl-CoA synthetase (LACS), were increased in a PPARα-dependent manner. This increased expression of LACS might enhance the fatty acyl-CoA supply to fatty acid degradation and sulfatide synthesis pathways. In fact, the first and last reactions in the sulfatide synthesis pathway are regulated by PPARα. Therefore, we also measured the expression levels of enzymes involved in sulfatide metabolism and the regulation of cellular sulfatide content. The levels of these enzymes and cellular sulfatide content both increased in a PPARα -dependent manner. These results indicate that PPARα activation plays defensive and compensative roles by reducing cellular toxicity associated with fatty acids and sulfuric acid.

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Inhibition of peroxisome-proliferator-activated receptor (PPAR)α by MK886

Cited by 127 publications

References 46 publications

Induction of Scavenger Receptor Class B Type I Is Critical for Simvastatin Enhancement of High-Density Lipoprotein-Induced Anti-Inflammatory Actions in Endothelial Cells

Induction of Scavenger Receptor Class B Type I Is Critical for Simvastatin Enhancement of High-Density Lipoprotein-Induced Anti-Inflammatory Actions in Endothelial Cells

Inhibition of Hepatic Glycogen Synthesis by Hyperhomocysteinemia Mediated by TRB3

Activation of PPAR<i>α</i> by Fatty Acid Accumulation Enhances Fatty Acid Degradation and Sulfatide Synthesis

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