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
Folic acid antioxidants were successfully intercalated into layered double hydroxides (LDH) nanoparticles according to a previous method with minor modification. The resultant folic acid-LDH constructs were then characterized by X-ray powder diffraction and transmission electron microscopy. The in vitro antioxidant activities, cytotoxicity effect, and in vivo antifatigue were examined by a series of assays. The results showed that folic acid-LDH antioxidant system can scavenge 1,1-diphenyl-2-picrylhydrazyl and hydroxyl free radicals and chelate pro-oxidative Cu 2+ . The in vitro cytotoxicity assays indicated that folic acid-LDH antioxidant system had no significant cytotoxic effect or obvious toxicity to normal cells. It also prolonged the forced swimming time of the mice by 32% and 51% compared to folic acid and control groups, respectively. It had an obvious effect on decreasing the blood urea nitrogen and blood lactic acid, while increasing muscle and hepatic glycogen levels. Therefore, folic acid-LDH might be used as a novel antioxidant and antifatigue nutritional supplement.
Background The β3-adrenoceptor (β3-AR) is implicated in cardiac remodeling. Since metabolic dysfunction due to loss of mitochondria plays an important role in heart diseases, we examined the effects of β3-AR on mitochondrial biogenesis and energy metabolism in atrial fibrillation (AF). Methods Atrial fibrillation was created by rapid atrial pacing in adult rabbits. Rabbits were randomly divided into 4 groups: control, pacing (P7), β3-AR antagonist (L748337), and β3-AR agonist (BRL37344) groups. Atrial effective refractory period (AERP) and AF induction rate were measured. Atrial concentrations of adenine nucleotides and phosphocreatine were quantified through high-performance liquid chromatography. Mitochondrial DNA content was determined. Real-time polymerase chain reaction and Western blot were used to examine the expression levels of signaling intermediates related to mitochondrial biogenesis. Results After pacing for 7 days, β3-AR was significantly upregulated, AERP was reduced, and the AF induction rate was increased. The total adenine nucleotides pool was significantly reduced due to the decrease in adenosine triphosphate (ATP). The P7 group showed decreased activity of F0F1-ATPase. Mitochondrial DNA content was decreased and mitochondrial respiratory chain subunits were downregulated after pacing. Furthermore, expression of transcription factors involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (Tfam), was lower in the P7 group in response to β3-AR activation. Further stimulation of β3-AR with BRL37344 exacerbated these effects, together with a significant decrease in the levels of phosphocreatine. In contrast, inhibition of β3-AR with L748337 partially restored mitochondrial biogenesis and energy metabolism of atria in the paced rabbits. Conclusion The activation of β3-AR contributes to atrial metabolic remodeling via transcriptional downregulation of PGC-1α/NRF-1/Tfam pathway that are involved in mitochondrial biogenesis, which ultimately perturbs mitochondrial function in rapid pacing-induced AF. The β3-AR is therefore a potential novel therapeutic target for the treatment or prevention of AF.
It is an extremely urgent problem that physical fitness promotion must face not only the increasing air pollution but also the decline of physical activity level of children and adolescents worldwide at present, which is the major reason that forms an inactive lifestyle and does harm to adolescents’ health. Thus, it is necessary to focus on the exposure factor in environmental health risk assessment (EHRA) which conducts supervision of environmental pollution and survey of adolescents’ activity patterns according to the harmful characteristics of air pollutant and relationship between dose and response. Some countries, such as USA, Canada and Australia, regard both respiratory rate and physical activity pattern as main exposure factors for adolescents in both air pollution health risk assessment and exercise risk assessment to forecast a safe exposing condition of pollutant for adolescents while they are doing exercise outdoors. In addition, it suggests that the testing indexes and testing methods of these two exposure factors, such as investigating the time of daily physical activity, strength, and characteristic of frequency, help to set up the quantitative relationship between environmental pollution index and the time, strength, frequency of daily activities, and formulate children’s and adolescents’ activity instructions under different levels of environmental pollutions. As smog becomes increasingly serious at present, it is meaningful to take physical activity as a critical composition of exposure factor and establish physical activity guideline, so as to reduce the risk of air pollution, and promote physical health of children and adolescents effectively.
The mechanism for different susceptibilities to obesity after short-term high-fat diet (HFD) feeding is largely unknown. Given the close association between obesity occurrence and mitochondrial dysfunction, the early events in skeletal muscle mitochondrial adaptations between HFD-induced obesity (DIO) and HFD-induced obesity resistant (DIO-R) lean phenotype under excess nutritional environment were explored.ICR/JCL male mice were randomly divided into 2 groups, as follows: low-fat diet (LFD) and HFD groups. After 6 weeks on HFD, HFD-fed mice were classified as DIO or DIO-R according to their body weight gain. Serum parameters, oxidative stress biomarkers, the activation of AMPK/ACC axis, and the expression profiles of mitochondrial biogenesis were measured by using corresponding methods among the LFD control, DIO, and DIO-R groups. Serum glucose, total cholesterol, low-density lipoprotein, and high-density lipoprotein levels were significantly increased in DIO and DIO-R mice compared with LFD controls. However, DIO-R mice had significantly higher MDA levels and exhibited a significantly higher level of AMP-activated protein kinase (AMPK) activation and acetyl-CoA carboxylase (ACC) inactivation than DIO mice. Furthermore, the transcript and protein levels of transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) and estrogen-related receptor-α (ERRα) in DIO-R mice were significantly up-regulated compared with the DIO mice. Although the body weight gain differed, the DIO and DIO-R mice had similar metabolic disturbance of glucose and lipids after short-term HFD consumption. The diverse alterations on fatty acid oxidation and mitochondrial biogenesis pathway induced by AMPK activation might be involved in different susceptibilities to obesity when consuming HFD.
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