Fenofibrate-Induced Muscular Toxicity Is Associated with a Metabolic Shift Limited to Type-1 Muscles in Rats

Okada, Mitsuru; Sano, Fumiko; Ikeda, Itsuko; Sugimoto, Jiro; Takagi, Shigeaki; Sakai, Hiroki; Yanai, Tokuma

doi:10.1177/0192623309336151

Cited by 15 publications

(15 citation statements)

References 24 publications

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“…Accumulating evidence suggesting that fenofibrate up‐regulates the expression of PDK4 and GLUT4 by activating PPAR‐α (Okada et al , ; Saito et al , ) and that resveratrol‐activated sirtuin 1 could suppress the activity of PDK4 to enhance PDH activity (Sin et al , ). Interestingly, in our study, fenofibrate suppressed the expression of PDK4 and increased the expression of PDH and GLUT4.…”

Section: Discussionmentioning

confidence: 99%

Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR‐α/sirtuin 1/PGC‐1α pathway

Liu

Hou

Yuan

et al. 2016

British J Pharmacology

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BACKGROUND AND PURPOSEAtrial metabolic remodelling is critical for the process of atrial fibrillation (AF). The PPAR-α/sirtuin 1 /PPAR co-activator α (PGC-1α) pathway plays an important role in maintaining energy metabolism. However, the effect of the PPAR-α agonist fenofibrate on AF is unclear. Therefore, the aim of this study was to determine the effect of fenofibrate on atrial metabolic remodelling in AF and explore its possible mechanisms of action. EXPERIMENTAL APPROACHThe expression of metabolic proteins was examined in the left atria of AF patients. Thirty-two rabbits were divided into sham, AF (pacing with 600 beats·min À1 for 1 week), fenofibrate treated (pretreated with fenofibrate before pacing) and fenofibrate alone treated (for 2 weeks) groups. HL-1 cells were subjected to rapid pacing in the presence or absence of fenofibrate, the PPAR-α antagonist GW6471 or sirtuin 1-specific inhibitor EX527. Metabolic factors, circulating biochemical metabolites, atrial electrophysiology, adenine nucleotide levels and accumulation of glycogen and lipid droplets were assessed. KEY RESULTSThe PPAR-α/sirtuin 1/PGC-1α pathway was significantly inhibited in AF patients and in the rabbit/HL-1 cell models, resulting in a reduction of key downstream metabolic factors; this effect was significantly restored by fenofibrate. Fenofibrate prevented the alterations in circulating biochemical metabolites, reduced the level of adenine nucleotides and accumulation of glycogen and lipid droplets, reversed the shortened atrial effective refractory period and increased risk of AF. CONCLUSION AND IMPLICATIONSFenofibrate inhibited atrial metabolic remodelling in AF by regulating the PPAR-α/sirtuin 1/PGC-1α pathway. The present study may provide a novel therapeutic strategy for AF. AbbreviationsAcAc, acetoacetate; AERP, atrial effective refractory period; AF, atrial fibrillation; BOH, β-hydroxybutyrate; FFA, free fatty acid; GLUT4, glucose transporter 4; GS1, glycogen synthase1; H-FABP, heart fatty acid binding protein; MCAD, medium-chain acylCoA dehydrogenase; mCPT-1, mitochondrial carnitine palmitoyltransferase1; PDH, pyruvate dehydrogenase; PDK4, pyruvate dehydrogenase kinase 4; PGC-1α, PPAR co-activator 1α; p-GS1, phosphorylated-GS1; TKB, total ketone body

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Section: Discussionmentioning

confidence: 99%

Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR‐α/sirtuin 1/PGC‐1α pathway

Liu

Hou

Yuan

et al. 2016

British J Pharmacology

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“…Although the protective effects of UDCA observed in this study were almost comparable to fenofibrate, however, UDCA might be preferable considering safety. Fibrates, although generally well tolerated, may cause myopathy and rhabdomyolysis both in humans [66] and rats [67]. In addition, some case studies described hepatotoxicity associated with fenofibrate [68], [69].…”

Section: Discussionmentioning

confidence: 99%

Ursodeoxycholic Acid Ameliorates Fructose-Induced Metabolic Syndrome in Rats

Mahmoud

Elshazly

2014

PLoS ONE

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The metabolic syndrome (MS) is characterized by insulin resistance, dyslipidemia and hypertension. It is associated with increased risk of cardiovascular diseases and type-2 diabetes. Consumption of fructose is linked to increased prevalence of MS. Ursodeoxycholic acid (UDCA) is a steroid bile acid with antioxidant, anti-inflammatory activities and has been shown to improve insulin resistance. The current study aims to investigate the effect of UDCA (150 mg/kg) on MS induced in rats by fructose administration (10%) in drinking water for 12 weeks. The effects of UDCA were compared to fenofibrate (100 mg/kg), an agonist of PPAR-α receptors. Treatment with UDCA or fenofibrate started from the 6th week after fructose administration once daily. Fructose administration resulted in significant increase in body weight, elevations of blood glucose, serum insulin, cholesterol, triglycerides, advanced glycation end products (AGEs), uric acid levels, insulin resistance index and blood pressure compared to control rats. Moreover, fructose increased oxidative stress in aortic tissues indicated by significant increases of malondialdehyde (MDA), expression of iNOS and reduction of reduced glutathione (GSH) content. These disturbances were associated with decreased eNOS expression, increased infiltration of leukocytes and loss of aortic vascular elasticity. Treatment with UDCA successfully ameliorated the deleterious effects of fructose. The protective effect of UDCA could be attributed to its ability to decrease uric acid level, improve insulin resistance and diminish oxidative stress in vascular tissues. These results might support possible clinical application of UDCA in MS patients especially those present with liver diseases, taking into account its tolerability and safety. However, further investigations on human subjects are needed before the clinical application of UDCA for this indication.

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“…Over recent years study of the muscle damage produced in rodents by lipid regulating drugs notably the fibrates and statins have shown that muscle fiber types vary in their sensitivity to xenobiotics ( 97 Schaefer et al 2004; 120 Westwood et al 2005; 26 De Souza et al 2006; 84 Okada et al 2007; 37 Faiola et al 2008; 122 Westwood et al 2008; 85 Okada et al 2009). It is important therefore to include both type 1 and type II fibers for histological assessment.…”

Section: Morphologymentioning

confidence: 99%

Proliferative and Non-Proliferative Lesions of the Rat and Mouse Soft Tissue, Skeletal Muscle and Mesothelium

et al. 2013

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The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in the soft tissues including skeletal muscle as well as the mesothelium of rats and mice. The standardized nomenclature of lesions presented in this document is also available electronically on the Internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous developmental and aging lesions as well as those induced by exposure to test materials. A widely accepted and utilized international harmonization of nomenclature for lesions in soft tissues, skeletal muscle and mesothelium in laboratory animals will decrease confusion among regulatory and scientific research organizations in different countries and provide a common language to increase and enrich international exchanges of information among toxicologists and pathologists. (DOI: 10.1293/tox.26.1S; J Toxicol Pathol 2013; 26: 1S–26S)

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Fenofibrate-Induced Muscular Toxicity Is Associated with a Metabolic Shift Limited to Type-1 Muscles in Rats

Cited by 15 publications

References 24 publications

Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR‐α/sirtuin 1/PGC‐1α pathway

Fenofibrate inhibits atrial metabolic remodelling in atrial fibrillation through PPAR‐α/sirtuin 1/PGC‐1α pathway

Ursodeoxycholic Acid Ameliorates Fructose-Induced Metabolic Syndrome in Rats

Proliferative and Non-Proliferative Lesions of the Rat and Mouse Soft Tissue, Skeletal Muscle and Mesothelium

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