Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator for management of atherogenic dyslipidaemia

Fruchart, Jean Charles

doi:10.1186/s12933-017-0602-y

Cited by 120 publications

(103 citation statements)

References 65 publications

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“…20,21 Pemafibrate, a novel selective PPARa modulator, has higher potency and subtype selectivity for PPARa than fenofibrate. 22 Phase 2 and 3 studies demonstrated that pemafibrate treatment, with or without statins, resulted in a significant decrease in fasting TG level and increase in HDL-C level and suggested that pemafibrate may have a superior risk/benefit profile to fenofibrate. [23][24][25][26][27] In vivo and in vitro studies found that pemafibrate enhanced CEC, RCT, and TRL catabolism, suppressed TRL production, and exerted anti-inflammatory and antiatherosclerotic effects.…”

Section: Introductionmentioning

confidence: 99%

Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia

Yamashita

Arai

Yokote

et al. 2018

Journal of Clinical Lipidology

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Section: Introductionmentioning

confidence: 99%

Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia

Yamashita

Arai

Yokote

et al. 2018

Journal of Clinical Lipidology

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“…5a). To further explore if targeted DNA demethylation of the Fgf21 promoter affected mRNA expression responses, we examined the impact of K-877, a novel selective PPARα modulator (SPPARMα) 18 www.nature.com/scientificreports www.nature.com/scientificreports/ response. Upon K-877 administration, Fgf21 mRNA expression was significantly increased, when transiently transfected with either gRNA1, gRNA2, or gRNA1+2 relative to scramble gRNA.…”

Section: Dnmt1 and Dnmt3a Contribute To Re-methylation In The Fgf21 Pmentioning

confidence: 99%

Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing

Hanzawa

Hashimoto

Yuan

et al. 2020

Sci Rep

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Recently, we reported ppARα-dependent DNA demethylation of the Fgf21 promoter in the postnatal mouse liver, where reduced DnA methylation is associated with enhanced gene expression after ppARα activation. However, there is no direct evidence for the effect of site-specific DNA methylation on gene expression. We employed the dCas9-SunTag and single-chain variable fragment (scFv)-TET1 catalytic domain (TET1CD) system to induce targeted DnA methylation of the Fgf21 promoter both in vitro and in vivo. We succeeded in targeted DnA demethylation of the Fgf 21 promoter both in Hepa1-6 cells and PPARα-deficient mice, with increased gene expression response to ppARα synthetic ligand administration and fasting, respectively. this study provides direct evidence that the DnA methylation status of a particular gene may determine the magnitude of the gene expression response to activation cues. In mammalian cells, DNA methylation is a major epigenetic modification, which regulates gene expression without alteration of the DNA sequence and thus plays a pivotal role in a myriad of physiological and pathological processes, including cell development and differentiation, genome imprinting, and tumorigenesis 1. We reported previously that the DNA methylation status of hepatic metabolic genes dynamically changes in early life, especially during the suckling period, thereby sequentially developing metabolic function in the liver to adapt to the drastic changes in the major nutrition source 2-4. Peroxisome proliferator-activated receptor-α (PPARα) is a nuclear receptor and a key regulator of hepatic lipid metabolism, which is activated by milk lipids as ligands at the onset of lactation. PPARα governs the transcription of major hepatic metabolism-related genes, and the activation of PPARα physiologically leads to DNA demethylation of fatty acid β-oxidation genes in the postnatal mouse liver 3,4. Of note, administration of a synthetic PPARα ligand to mouse dams during the perinatal period induced enhanced reduction of DNA methylation of PPARα target genes in the offspring liver, suggesting that the DNA methylation status of PPARα target genes can be modulated with ease during the perinatal period 3,4. A genome-wide analysis of DNA methylation revealed that a few PPARα target genes undergo ligand-activated, PPARα-dependent DNA demethylation during the perinatal period, and the DNA hypomethylation status of these persists into adulthood. Among these genes, which may be referred to as "epigenetic memory genes," we focused on fibroblast growth factor 21 (FGF21), which is a metabolic hormone derived from the liver and a master regulator of glucose and lipid metabolism 5-7 .

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“…It is primarily liver eliminated, whereas fenofibrate, gemfibrozil and bezafibrate have a predominant kidney elimination. 77 Phase 2 studies. The effectiveness of pemafibrate was evaluated in patients on statins (JapicCTI-121837 and JapicCTI-132067).…”

Section: Ppar-modulator -Pemafibratementioning

confidence: 99%

Recent advances in synthetic pharmacotherapies for dyslipidaemias

Sirtori

Yamashita

Greco

et al. 2019

Eur J Prev Cardiolog

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Despite the demonstrated benefits of statins and injectable biologics, there is a need for new and safe oral agents for addressing classical lipid targets, low-density lipoprotein cholesterol (LDL-C), triglycerides and high-density lipoprotein cholesterol (HDL-C). LDL-C is unquestionably causal in the development of atherogenesis and atherosclerotic cardiovascular disease, but new options are required to address triglyceride-rich lipoproteins and lipoprotein(a). For hypercholesterolaemia, pitavastatin provides a very low dose and potent statin that does not adversely affect glucose metabolism; bempedoic acid acts at a biochemical step preceding hydroxymethylglutaryl-CoA reductase and is not associated with muscular side effects. For hypertriglyceridaemia, pemafibrate displays a unique and selective agonist activity on peroxisomal proliferator activated receptor-α that does not elevate homocysteine or creatinine. Although omega-3 fatty acids supplementation is not effective in secondary prevention, high dose eicosapentaenoic ethyl ester can lead to a remarkable fall in first and recurrent events in high risk patients with hypertriglyceridaemia/low HDL-C. Gemcabene, a dicarboxylic acid regulating apolipoprotein B-100, is effective in reducing both cholesterol and triglycerides. Among cholesteryl ester transfer protein antagonists that elevate HDL-C, only anacetrapib reduces cardiovascular events. Probucol stimulates reverse cholesteryl ester transport, lowers LDL-C stabilizing plaques and may lower incidence of cardiovascular events. These agents, which act through novel mechanisms, afford good and potentially safe treatment choices that may increase adherence and the attainment of therapeutic targets.

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Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator for management of atherogenic dyslipidaemia

Cited by 120 publications

References 65 publications

Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia

Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia

Targeted DNA demethylation of the Fgf21 promoter by CRISPR/dCas9-mediated epigenome editing

Recent advances in synthetic pharmacotherapies for dyslipidaemias

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