Peroxisome proliferator-activated receptor δ

Bojic, Lazar A.; Huff, Murray W.

doi:10.1097/mol.0b013e32835cc949

Cited by 78 publications

(35 citation statements)

References 54 publications

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“…The concentrations of the PPAR agonists were used as published and do not induce any cytotoxicity as previously shown [12, 20, 26–29]. Treatment of non-stimulated HUVECs with each agonist resulted in an induction of ICAM-1 surface expression (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…Recent evidence suggests that PPARδ plays a crucial role in the regulation of differentiation, cell growth, and the metabolism of lipids and glucose [8–11]. Previous studies demonstrated that PPARδ agonists improve insulin sensitivity and therefore might be interesting targets for the treatment of obesity-associated disorders [12–14]. …”

Section: Introductionmentioning

confidence: 99%

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Peroxisome proliferator-activated receptor (PPAR) α and δ activators induce ICAM-1 expression in quiescent non stimulated endothelial cells

et al. 2016

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BackgroundPeroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are implicated in the regulation of lipid and glucose homeostasis. PPAR agonists have been shown to control inflammatory processes, in part by inhibiting the expression of distinct proinflammatory genes such as vascular cell adhesion molecule-1 (VCAM-1), IL-8, and intercellular adhesion molecule-1 (ICAM-1). ICAM-1 is an important endothelial membrane receptor that facilitates the transmigration of leukocytes across the endothelium. To date, the influence of PPARα and δ activators on the expression of ICAM-1 in non-induced, quiescent endothelial cells has been unclear. Therefore, we examined the effects of various PPARα and δ agonists on the expression of ICAM-1 in non-stimulated primary human endothelial cells.ResultsWe found that PPARα and PPARδ agonists significantly induced ICAM-1 surface, intracellular protein, and mRNA expression in a time and concentration-dependent manner. The PPARδ induced ICAM-1 expression could be paralleled with a significantly increased T-cell adherence to the endothelial cells whereas PPARα failed to do so. Transcriptional activity studies using an ICAM-1 reporter gene constructs revealed that PPARδ, but not PPARα agonists induced gene expression by stimulating ICAM-1 promoter activity via an Sp1 transcription factor binding site and inhibit the binding of the transcription factors Sp1 and Sp3. Furthermore, we performed mRNA stability assays and found that PPARα and PPARδ agonists increased ICAM-1 mRNA stability.ConclusionTherefore, our data provide the first evidence that PPARα and PPARδ agonists induce ICAM-1 expression in non-stimulated endothelial cells via transcriptional and posttranscriptional mechanisms.

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Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Peroxisome proliferator-activated receptor (PPAR) α and δ activators induce ICAM-1 expression in quiescent non stimulated endothelial cells

et al. 2016

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“…Fibrates, which are synthetic agonists of PPARα, are used extensively for clinical treatment of hypertriglyceridemia, but have not shown a consistent beneficial effect for the treatment of NAFLD,18 possibly related to their effect on PPARα outside the liver. PPARδ, another member of the PPAR family, has a wider expression distribution pattern, and beyond hepatocytes is also expressed in high levels in skeletal muscle and macrophages19 and its activation improves insulin sensitivity, decreases hepatic glucose production, increases fatty acid oxidation and decreases macrophage and Kupffer cell activation. PPARδ activation has also been shown to decrease atherosclerotic disease in animal models 20.…”

Section: Medications With a Primary Metabolic Targetmentioning

confidence: 99%

Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease

Rotman

Sanyal

2016

Gut

350

294

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Given the high prevalence and rising incidence of non-alcoholic fatty liver disease (NAFLD), the absence of approved therapies is striking. Although the mainstay of treatment of NAFLD is weight loss, it is hard to maintain, prompting the need for pharmacotherapy as well. A greater understanding of disease pathogenesis in recent years was followed by development of new classes of medications, as well as potential repurposing of currently available agents. NAFLD therapies target four main pathways. The dominant approach is targeting hepatic fat accumulation and the resultant metabolic stress. Medications in this group include peroxisome proliferator-activator receptor agonists (eg, pioglitazone, elafibranor, saroglitazar), medications targeting the bile acid-farnesoid X receptor axis (obeticholic acid), inhibitors of de novo lipogenesis (aramchol, NDI-010976), incretins (liraglutide) and fibroblast growth factor (FGF)-21 or FGF-19 analogues. A second approach is targeting the oxidative stress, inflammation and injury that follow the metabolic stress. Medications from this group include antioxidants (vitamin E), medications with a target in the tumour necrosis factor α pathway (emricasan, pentoxifylline) and immune modulators (amlexanox, cenicriviroc). A third group has a target in the gut, including antiobesity agents such as orlistat or gut microbiome modulators (IMM-124e, faecal microbial transplant, solithromycin). Finally, as the ongoing injury leads to fibrosis, the harbinger of liver-related morbidity and mortality, antifibrotics (simtuzumab and GR-MD-02) will be an important element of therapy. It is very likely that in the next few years several medications will be available to clinicians treating patients with NAFLD across the entire spectrum of disease.

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“…There is a possibility that selective PPAR modulators may overcome some of these limitations, but progress has been rather slow. PPARα activation has the potential to enhance fatty acid oxidation and lipid catabolism and improve insulin resistance as well as inflammation [62]. Of potential interest for further development is MBX-8025, a selective PPARδ agonist which improves insulin resistance and liver function [63].…”

Section: Targeting Nuclear Receptor-mediated Mechanisms Participatmentioning

confidence: 99%

New Medical Treatment Strategies for Nonalcoholic Steatohepatitis

Fuchs

2015

Curr Treat Options Gastro

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Nonalcoholic steatohepatitis (NASH) is a severe form of fatty liver disease unrelated to chronic alcohol consumption. As nonalcoholic fatty liver disease (NAFLD) has reached epidemic proportions and is becoming the most common cause for chronic liver disease, NASH likely will replace chronic hepatitis C as leading indication for liver cirrhosis and liver transplantation in this decade. Despite this alarming trend, effective treatment is lacking and continues to rely on dietary interventions and physical exercise, known to be of limited effect. Hence, there is an urgent need for safe pharmacologic therapy that successfully reverses or prevents progression of liver injury and fibrosis in patients with NASH. Employing emerging concepts of disease development and progression that involve in parallel ongoing events originating from the liver, adipose tissue, and intestine will ultimately promote the development of effective agents for targeted therapies for NASH. Novel agents must be safe, optimally dosed, and finally pass clinical trials providing proof of concept and efficacy. In the case of NASH, trial design is not necessarily straightforward as surrogate end points to predict clinical benefits are not yet established. The level of unmet needs for NASH goes however even beyond therapeutic agents and also includes patient and physician awareness. This article focuses on identifying potential pathophysiology-guided targets for medical therapy of NASH.

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Peroxisome proliferator-activated receptor δ

Abstract: Recent advances in the understanding of PPARδ reveal that activation of this receptor represents a multifaceted therapeutic strategy for the prevention and treatment of insulin-resistant syndromes and atherosclerosis.

Cited by 78 publications

References 54 publications

Peroxisome proliferator-activated receptor (PPAR) α and δ activators induce ICAM-1 expression in quiescent non stimulated endothelial cells

Peroxisome proliferator-activated receptor (PPAR) α and δ activators induce ICAM-1 expression in quiescent non stimulated endothelial cells

Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease

New Medical Treatment Strategies for Nonalcoholic Steatohepatitis

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