Effects Of Bezafibrate Research Articles

Efficacy and Safety of Bezafibrate Alone or in Combination with Ursodeoxycholic Acid in Primary Biliary Cholangitis: Systematic Review and Meta-Analysis.

Bezafibrate (BZF) alone or in combination with ursodeoxycholic acid (UDCA) has been used to slow disease progression in patients with primary biliary cholangitis (PBC). We performed a systematic review and meta-analysis to assess the efficacy and harms of BZF monotherapy or combination therapy. We performed a systematic search of PubMed, EMBASE, Cochrane Library, Scopus, ClinicalTrials.gov, and WHO ICTRP from inception until January 2020, for randomized controlled clinical trials assessing BZF + UDCA versus UDCA monotherapy or BZF monotherapy versus UDCA monotherapy in PBC patients. Additionally, we systematically evaluated data on harms using seven observational studies. Pooled effect estimates were calculated for the outcomes of interest. The certainty of evidence was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). We identified 7 randomized controlled trials with a total of 279 participants. Comparing BZF + UDCA to UDCA alone, a clinically significant improvement was observed in serum ALP with a mean difference (MD) of - 159.04 U/L (95% CI - 186.45 to - 131.62) and a reduction in gamma-glutamyltransferase (GGT) (MD - 106.94IU/L; 95% CI - 151.99 to - 61.89), but not in total bilirubin (TB) or IgM levels. A statistically significant reduction in ALP levels was also noticed with BZF monotherapy compared to UDCA monotherapy. The effect of BZF + UDCA versus UDCA on mortality remains unclear. Across 5 observational studies including 106 patients, one death was reported due to advanced liver disease in an incomplete responder getting treatment with BZF + UDCA. Analysis of observational studies demonstrated improvement in pruritus intensity with BZF. Use of BZF alone or in combination with UDCA improved liver biochemistries in patients with PBC, but its effect on mortality, liver-related complications or quality of life remains unknown.

Effects of Bezafibrate on Carbon Tetrachloride and T0901317-Induced Nonalcoholic Steatohepatitis Model

To date, we have established a non-alcoholic steatohepatitis (NASH) model by feeding rats and mice a choline-deficient amino acid diet or a high-fat diet. However, it has been pointed out that it takes a long time to prepare the model and that the extrapolation to humans is low. Therefore, we confirmed the reproducibility of the NASH model, which develops in a short period of time, by referring to the method of Ohkohchi et al., and whether bezafibrate is effective for this model.

Efficacy of bezafibrate for preventing myopathic attacks in patients with very long-chain acyl-CoA dehydrogenase deficiency

BackgroundVery long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is a mitochondrial fatty acid oxidation disorder that causes episodic attacks, such as general fatigue, hypotonia, myalgia, and rhabdomyolysis accompanied by lack of energy. As yet, there are no preventative drugs for these VLCADD-associated metabolic attacks. Patients and methodsWe conducted an open-label, non-randomized, multi-center study into the effects of bezafibrate on five patients with VLCADD. Bezafibrate was administered for 4 years, and we analyzed the number of myopathic attacks requiring hospitalization and treatment infusions. ResultsThe number of myopathic attacks requiring infusions of 24 h or longer significantly decreased during the study period. The patients’ ability to conduct everyday activities was also improved by the treatment. ConclusionOur findings show the potential long-term efficacy of bezafibrate in preventing myopathic attacks for patients with VLCADD.

Effect of Bezafibrate on Deoxyribonucleic Acid in the Presence of Iron and Copper

Effect of Bezafibrate on Deoxyribonucleic Acid in the Presence of Iron and Copper

Bezafibrate Upregulates Mitochondrial Biogenesis and Influence Neural Differentiation of Human-Induced Pluripotent Stem Cells

Bezafibrate (BZ) regulates mitochondrial biogenesis by activation of PPAR’s receptors and enhancing the level of PGC-1α coactivator. In this report, we investigated the effect of BZ on the expression of genes (1) that are linked to different pathways involved in mitochondrial biogenesis, e.g., regulated by PPAR’s receptors or PGC-1α coactivator, and (2) involved in neuronal or astroglial fate, during neural differentiation of hiPSC. The tested cell populations included hiPSC-derived neural stem cells (NSC), early neural progenitors (eNP), and neural progenitors (NP). RNA-seq analysis showed the expression of PPARA, PPARD receptors and excluded PPARG in all tested populations. The expression of PPARGC1A encoding PGC-1α was dependent on the stage of differentiation: NSC, eNP, and NP differed significantly as compared to hiPSC. In addition, BZ-evoked upregulation of PPARGC1A, GFAP, S100B, and DCX genes coexist with downregulation of MAP2 gene only at the eNP stage of differentiation. In the second task, we investigated the cell sensitivity and mitochondrial biogenesis upon BZ treatment. BZ influenced the cell viability, ROS level, mitochondrial membrane potential, and total cell number in concentration- and stage of differentiation-dependent manner. Induction of mitochondrial biogenesis evoked by BZ determined by the changes in the level of SDHA and COX-1 protein, and mtDNA copy number, as well as the expression of NRF1, PPARGC1A, and TFAM genes, was detected only at NP stage for all tested markers. Thus, developmental stage-specific sensitivity to BZ of neurally differentiating hiPSC can be linked to mitochondrial biogenesis, while fate commitment decisions to PGC-1α (encoded by PPARGC1A) pathway.

Bezafibrate Prevents Glycine-Induced Increase of Antioxidant Enzyme Activities in Rat Striatum.

Non-ketotic hyperglycinemia (NKH) is a severe neurological disorder caused by defects in glycine (GLY) catabolism and characterized by a high cerebrospinal fluid/plasma GLY ratio. Treatment is often ineffective and limited to the control of symptoms and detoxification of GLY. In the present work, we investigated the in vivo effects of GLY intracerebroventricular administration on oxidative stress parameters in rat striatum, cerebral cortex, and hippocampus. In vitro effects of GLY were also evaluated in striatum. The effects of bezafibrate (BEZ), a potential neuroprotective agent, on the possible alterations caused by GLY administration were further evaluated. Our in vivo results showed that GLY increased the activities of the antioxidant enzymes superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), and glucose-6-phosphate dehydrogenase (G6PDH) in striatum. Furthermore, GLY decreased the concentrations of total glutathione and reduced glutathione (GSH), as well as GSH/oxidized glutathione ratio in vivo in hippocampus. In vitro data also showed that GLY induced lipid peroxidation and decreased GSH in striatum. Regarding the effects of BEZ, we found that GLY-induced increase of GPx, SOD, and GR activities was attenuated or prevented by this compound. However, BEZ did not alter GLY-induced decrease of GSH in hippocampus. We hypothesize that GLY-induced increase of the activities of antioxidant enzymes in striatum occurs as a mechanism to avoid accumulation of reactive oxygen species and consequent oxidative damage. Furthermore, since BEZ prevented GLY-induced alterations, it might be considered as an adjuvant therapy for NKH.

Effects of Bezafibrate on Outcome and Pruritus in Primary Biliary Cholangitis With Suboptimal Ursodeoxycholic Acid Response.

Adding fibrates improves liver biochemistries in patients with primary biliary cholangitis (PBC) and suboptimal response to ursodeoxycholic acid (UDCA). As there are no consistent data regarding the course and outcome, we have assessed the effects of the combined treatment with UDCA and bezafibrate on a long-term basis. A total of 48 patients (45 female) with PBC treated with UDCA and alkaline phosphatase (ALP) above 1.5 times upper normal levels (× UNL) were treated with bezafibrate (400 mg/day) plus UDCA (13-16 mg/kg/day). Changes in clinical features, liver biochemistries, and prognosis after therapy were assessed, as well as pruritus, using a visual analog scale (43 patients) and the 5-D descriptive pruritus scale. After a median of 38 months, 26 patients (54%) had normalized ALP. In these patients, jaundice, pruritus, and liver stiffness was lower, and age was higher than in patients who remained with elevated ALP. Biochemical improvement was less prominent in patients without ALP normalization. Five of these patients (23%) developed events of disease progression: 1 died, 3 were transplanted, and 1 developed hepatocellular carcinoma. Partial or complete itching relief was reported in all but one case with pruritus. Itching recurrence or worsening was observed after bezafibrate discontinuation. The long-term treatment with UDCA and bezafibrate results in excellent response, and is associated with a complete or partial itching relief. Incomplete ALP normalization was observed in patients with advanced disease who remained at risk for developing severe events. The combined treatment is mainly effective in patients with lower fibrosis and severity of cholestasis.

The PPAR pan-agonist bezafibrate ameliorates cardiomyopathy in a mouse model of Barth syndrome

BackgroundThe PGC-1α/PPAR axis has been proposed as a potential therapeutic target for several metabolic disorders. The aim was to evaluate the efficacy of the pan-PPAR agonist, bezafibrate, in tafazzin knockdown mice (TazKD), a mouse model of Barth syndrome that exhibits age-dependent dilated cardiomyopathy with left ventricular (LV) dysfunction.ResultsThe effect of bezafibrate on cardiac function was evaluated by echocardiography in TazKD mice with or without beta-adrenergic stress. Adrenergic stress by chronic isoproterenol infusion exacerbates the cardiac phenotype in TazKD mice, significantly depressing LV systolic function by 4.5 months of age. Bezafibrate intake over 2 months substantially ameliorates the development of LV systolic dysfunction in isoproterenol-stressed TazKD mice. Without beta-adrenergic stress, TazKD mice develop dilated cardiomyopathy by 7 months of age. Prolonged treatment with suprapharmacological dose of bezafibrate (0.5% in rodent diet) over a 4-month period effectively prevented LV dilation in mice isoproterenol treatment. Bezafibrate increased mitochondrial biogenesis, however also promoted oxidative stress in cardiomyocytes. Surprisingly, improvement of systolic function in bezafibrate-treated mice was accompanied with simultaneous reduction of cardiolipin content and increase of monolysocardiolipin levels in cardiac muscle.ConclusionsThus, we demonstrate that bezafibrate has a potent therapeutic effect on preventing cardiac dysfunction in a mouse model of Barth syndrome with obvious implications for treating the human disease. Additional studies are needed to assess the potential benefits of PPAR agonists in humans with Barth syndrome.

Bezafibrate for the treatment of dyslipidemia in patients with coronary artery disease: 20-year mortality follow-up of the BIP randomized control trial.

BackgroundRecent data support the renewed interest in hypertriglyceridemia as a possible important therapeutic target for cardiovascular risk reduction. This study was designed to address the question of all-cause mortality during extended follow-up of the BIP trial in patients stratified by baseline triglyceride levels.MethodsIn the BIP trial 3090 patients with proven coronary artery disease were randomized to bezafibrate 400 mg/day or placebo. All-cause mortality data after 20 years of follow-up, were obtained from the National Israeli Population Registry. Patients with hypertriglyceridemia (triglycerides ≥200 mg/dL, n = 458) were equally distributed among the study groups (15 % in both placebo and bezafibrate groups).ResultsDuring follow-up 1869 patients died (952 in placebo vs. 917 in bezafibrate group). Following multivariate adjustment allocation to bezafibrate was associated with small but significant 10 % mortality risk reduction (HR 0.90; 95 % CI 0.82–0.98, p = 0.026). Variables associated with significantly increased mortality risk were history of a past MI, NYHA class, diabetes, age, higher BMI and glucose level. In patients with hypertriglyceridemia multivariate analysis demonstrated a 25 % all-cause mortality risk reduction associated with allocation to bezafibrate (HR 0.75, CI 95 % 0.60–0.94; p = 0.012). In patients without hypertriglyceridemia bezafibrate had no significant effect on long-term mortality.ConclusionsDuring long-term follow-up bezafibrate-allocated patients experienced a modest but significant 10 % reduction in the adjusted risk of mortality. This effect of bezafibrate was more prominent among patients with baseline hypertriglyceridemia (25 % mortality risk reduction).Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-016-0332-6) contains supplementary material, which is available to authorized users.

Mitochondrial trifunctional protein deficiency in human cultured fibroblasts: effects of bezafibrate.

Mitochondrial trifunctional protein (MTP) deficiency caused by HADHA or HADHB gene mutations exhibits substantial molecular, biochemical, and clinical heterogeneity and ranks among the more severe fatty acid oxidation (FAO) disorders, without pharmacological treatment. Since bezafibrate has been shown to potentially correct other FAO disorders in patient cells, we analyzed its effects in 26 MTP-deficient patient fibroblasts representing 16 genotypes. Overall, the patient cell lines exhibited variable, complex, biochemical profiles and pharmacological responses. HADHA-deficient fibroblasts showed markedly reduced alpha subunit protein levels together with decreased beta-subunit abundance, exhibited a -86 to -96% defect in LCHAD activity, and produced large amounts of C14 and C16 hydroxyacylcarnitines. In control fibroblasts, exposure to bezafibrate (400 μM for 48 h) increased the abundance of HADHA and HADHB mRNAs, immune-detectable alpha and beta subunit proteins, activities of LCHAD and LCKAT, and stimulated FAO capacities, clearly indicating that MTP is pharmacologically up-regulated by bezafibrate in human fibroblasts. In MTP-deficient patient fibroblasts, which were found markedly FAO-deficient, bezafibrate improved FAO capacities in six of 26 (23%) cases, including three cell lines heterozygous for the common c1528G > C mutation. Altogether, our results strongly suggest that, due to variable effects of HADHA and HADHB mutations on MTP abundance and residual activity, improvement of MTP deficiency in response to bezafibrate was achieved in a subset of responsive genotypes.

Bezafibrate treatment is associated with a reduced rate of re-hospitalization in smokers after acute coronary syndrome

Significantly increased rate of hospitalizations in current smokers is a major smoking-related problem which is associated with a heavy economic burden, whereas cardiovascular disease accounted for nearly half of hospitalizations. The effect of bezafibrate on the rate of re-hospitalization in smokers already treated with statin immediately post-acute coronary syndrome (ACS) is unknown. The aim of this study was to investigate 30-day rate of re-hospitalization in current smokers participating in the ACS Israeli Surveys (ACSIS) and who were treated on discharge with a bezafibrate/statin combination vs. statin alone. The study population comprised 3392 patients with confirmed current smoking status from the ACSIS 2000, 2002, 2004, 2006, 2008 and 2010 enrollment waves who were alive on discharge and received statin. Of these, 3189 (94%) were discharged with statin alone, 203 (6%) with a combination of a statin and bezafibrate. Thirty-day re-hospitalization rate was significantly lower in patients from the combination group than in their counterparts from the statin monotherapy group: 12.8% vs. 19%, p = 0.028. Multivariable analysis identified the combined bezafibrate/statin treatment as an independent predictor of reduced risk of 30-day re-hospitalization rate with odds ratio (OR) 0.53 (95% confidence interval [CI] 0.31-0.91), and it corresponded to 47% risk reduction. Other significant variables in our model associated with independent risk of 30-day re-hospitalization rate during the follow-up were female gender (OR 1.43, CI 1.05-1.95, p = 0.03) and age > 65 years (OR 1.49, CI 1.13-1.95, p = 0.004). Adding bezafibrate to statin in smokers was associated with a significantly reduced 30-day rate of re-hospitalization after ACS.

Comparison between effects of bezafibrate and eicosapentaenoic acid on arterial stiffness monitoring with cardio-ankle vascular index

Comparison between effects of bezafibrate and eicosapentaenoic acid on arterial stiffness monitoring with cardio-ankle vascular index

Bezafibrate Causes Depression of the Immune Response and Increases the Sensitivity to Endotoxin in Association with Low Level of HDL and PPARα Activity in Hypertensive ISIAH Rats

We studied the effect of bezafibrate on hepatic PPARα activity and immune parameters in hypertensive ISIAH rats in comparison with normotensive WAG rats under conditions of LPS treatment. Bezafibrate increased activity of PPARα in WAG rats, but not in ISIAH rats. As differentiated from WAG rats, bezafibrate produced a potent effect on the content of T cell subpopulations in the thymus and spleen of ISIAH rats. Administration of LPS after injection of bezafibrate caused death of 50% ISIAH animals (but not WAG rats), which was associated with low level of HDL cholesterol and increased triglyceride content. Our results suggest that the hypolipidemic treatment (e.g., bezafibrate) can increase the severity of complications in patients with infectious and inflammatory diseases in association with low level of HDL.

Activation of peroxisome proliferator-activated receptor-α (PPARα) in proximal intestine improves postprandial lipidemia in obese diabetic KK-Ay mice

Postprandial lipidemia is a risk factor for cardiovascular diseases. Thus, the suppression of postprandial lipidemia is valuable for disease management. Peroxisome proliferator-activated receptor- (PPAR ) is a key regulator in the lipid metabolism of peripheral tissues such as the liver and skeletal muscle, whose activation enhances fatty acid oxidation and decreases circulating lipid level. Recently, we have shown that bezafibrate, an agonistic compound for PPAR , suppresses post-prandial lipidemia by enhancing fatty acid oxidation in intestinal epithelial cells under physiological conditions. However, it was not elucidated whether the effect of PPAR on postprandial lipidemia is also observed under obese conditions, which change lipid metabolisms in various tissues and cells. Here, we observed that bezafibrate enhanced fatty acid oxidation in intestinal epithelial cells of obese diabetic KK-Ay mice. Bezafibrate treatment increased the mRNA expression levels of fatty acid oxidation-related genes, which are targets of PPAR , and enhanced CO2 production from [14C]-palmitic acid. The bezafibrate-treated mice showed the suppression of increasing serum triacylglyceride level after the oral administration of olive oil. Moreover, the effects of bezafibrate on mRNA expression and fatty acid oxidation were shown in only the proximal intestinal epithelial cells. These findings indicate that PPAR activation suppresses postprandial lipidemia under obese conditions through the enhancement of fatty acid oxidation, and that only the proximal intestine con-tributes to the effects in mice, suggesting that intestinal PPAR can be a target for prevention of obese-induced postprandial lipidemia.

THU0230 Bezafitrate for Methotorexate-Induced Acute Liver Injur\\y

BackgroundMethotrexate (MTX) is an anchor drug widely used in rheumatoid arthritis (RA). Higher dosage of MTX leads to more favorable outcome and its dose-dependent toxicity, therefore has gained much more...

Biochemical Alterations and Endothelial Dysfunction in Hypercholesterolemic Rats: Effects of Bezafibrate

Background: Hypercholesterolemia is a serious problem cause biohazards for human health and endothelial dysfunction. Objective: The current study was conducted to test effects of hyperlipidemia alone or in combination with bezafibrate at various doses. Total cholesterol, triacylglecerol, high density lipoprotein (HDL), low density lipoprotein (LDL), apolipoprotein B, endothelin-1, histamine, nitric oxide (NO), IL-6, creatinine and alanine amino transferase (ALT) were assayed Methodology: Rats were randomly divided into four groups (10 rats each). The first group fed a normal diet and represents the control group. The second group fed normal diet enriched with 1% cholesterol and 5% coconut oil (cholesterol-fed group). The third group fed on normal diet and bezafibrate at a dose of 100 mg/kg/day. The fourth group is cholesterol fed and subdivided into A, B, C and supplemented with bezafibrate at various concentration 50, 100, 200 mg/kg/day respectively. Feeding was continued daily for 6 weeks after incidence of hypercholesterolemia. Results: The current study revealed that total cholesterol, triacylglycerols, apolipoprotein B, and LDL concentration were significantly elevated in the cholesterol-fed rats compared to control alone and control plus bezafibrate. In addition, plasma endothelin-1, histamine and IL-6 concentration were significantly elevated in the cholesterol-fed rats compared to bezafibrate and control group rats. Bezafibrate administration to rats fed high cholesterol diet normalized significantly the changes in all parameters except NO levels compared to hyperlipidemic group. Meanwhile, the plasma nitric oxide in all groups was not significantly different from those of control. However, plasma HDL concentration in the cholesterol fed rats was significantly lowered compared to bezafibrate treated rats. Conclusion: Bezafibrate may acts as a mixed blessing drug to normalize lipid profiles and endothelial dysfunction during hyperlipidemia. © 2013 GESDAV

Pan-PPAR Agonist, Bezafibrate, Restores Angiogenesis in Hindlimb Ischemia in Normal and Diabetic Rats

Introduction. The aim of this study was to investigate the effect of bezafibrate as a pan-PPAR agonist on angiogenesis and serum nitrite, the main metabolite of nitric oxide (NO), vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) concentrations in hindlimb ischemia model of normal and type I diabetic rats. Methods. 28 male Wistar rats were divided into control and diabetic groups. Then, all rats underwent unilateral hindlimb ischemia. After recovery, they were randomly assigned to one of the following experimental groups: (1) control; (2) control + bezafibrate (400 mg/kg/day); (3) diabetic; (4) diabetic + beztafibrate. After three weeks, blood samples were taken and capillary density was evaluated in the gasterocnemius muscle of ischemic limb. Results. Bezafibrate increased capillary density and capillary/fiber ratio in ischemic leg of diabetic and control rats (P < 0.05). Serum VEGF and VEGFR-2 concentrations did not alter after bezafibrate administration, however, serum nitrite concentration was significantly higher in bezafibrate-treated groups than non-treated groups (P < 0.05). Discussion. It seems that bezafibrate, as a pan PPAR agonist, restores angiogenesis in hindlimb ischemic diabetic animals and is useful for prevention and/or treatment of peripheral artery disease in diabetic subjects.

Conditional Expression of Human PPARδand a Dominant Negative Variant of hPPARδ In Vivo

The nuclear receptor, NR1C2 or peroxisome proliferator-activated receptor (PPAR)-δ, is ubiquitously expressed and important for placental development, fatty acid metabolism, wound healing, inflammation, and tumour development. PPARδ has been hypothesized to function as both a ligand activated transcription factor and a repressor of transcription in the absence of agonist. In this paper, treatment of mice conditionally expressing human PPARδ with GW501516 resulted in a marked loss in body weight that was not evident in nontransgenic animals or animals expressing a dominant negative derivative of PPARδ. Expression of either functional or dominant negative hPPARδ blocked bezafibrate-induced PPARα-dependent hepatomegaly and blocked the effect of bezafibrate on the transcription of PPARα target genes. These data demonstrate, for the first time, that PPARδ could inhibit the activation of PPARα in vivo and provide novel models for the investigation of the role of PPARδ in pathophysiology.

Effect of Bezafibrate on Monocyte Cytokine Release and Systemic Inflammation in Patients With Impaired Fasting Glucose

This study assessed the effect of bezafibrate on monocyte secretory function and systemic inflammation in patients with impaired fasting glucose (IFG), comparing this effect with that produced by bezafibrate in mixed dyslipidemic subjects. The study included 28 patients with IFG, 29 individuals with mixed dyslipidemia, and 24 age-, sex- and weight-matched control subjects without lipid and glucose metabolism abnormalities. Compared with the control group, in both IFG and mixed dyslipidemic subjects, monocyte release of monocyte chemoattractant protein-1 (MCP-1), interleukin-6, tumor necrosis factor-α (TNF-α), and interleukin-1β was increased, which was accompanied by higher plasma levels of high-sensitivity C-reactive protein (hsCRP). Despite affecting plasma lipids in both treatment groups, bezafibrate administration (200 mg twice daily for 90 days) reduced fasting plasma glucose levels, the homeostasis model assessment index, and glycated hemoglobin only in IFG subjects. Bezafibrate treatment normalized monocyte release of MCP-1, interleukin-6, TNF-α, and interleukin-1β and also normalized plasma hsCRP levels in mixed dyslipidemic subjects, whereas in IFG individuals the drug reduced only MCP-1 and interleukin-6 release. This study shows that IFG is associated with the presence of systemic inflammation and abnormal monocyte secretory function. Compared with patients with mixed dyslipidemia, IFG patients who are administered bezafibrate experience a stronger effect on glucose metabolism and weaker anti-inflammatory and monocyte-suppressing actions.

Bezafibrate Restores the Inhibition of FSH-Induced Follicular Development and Steroidogenesis by Tumor Necrosis Factor-Alpha Through Peroxisome Proliferator-Activated Receptor-Gamma Pathway in an In Vitro Mouse Preantral Follicle Culture1

We recently reported that bezafibrate, a lipid-lowering drug of the fibrate class, administered in addition to clomiphene citrate (CC) successfully induced ovulation in CC-resistant polycystic ovary syndrome (PCOS) patients. We hypothesized that bezafibrate may directly affect ovarian follicle development. Insulin resistance and compensatory hyperinsulinemia are important for the pathogenesis of PCOS. In this study, we first examined the effects of tumor necrosis factor-alpha (TNF), which plays a role in insulin resistance, on follicle development by using the follicle culture system. TNF significantly inhibited follicle-stimulating hormone (FSH)-induced follicle development, 17beta-estradiol (E2) secretion, and ovulation rate in a dose-dependent manner. We then examined whether bezafibrate treatment could rescue the inhibition of FSH-induced follicle development and steroidogenesis by TNF. Bezafibrate treatment rescued inhibition of follicle development, secretion of E2, and ovulation rate by TNF. We examined the expression of peroxisome proliferator-activated receptor (PPAR) subtypes in mouse preantral follicles. As the protein expression of only PPARG was observed in mouse preantral follicles, we examined whether bezafibrate could affect follicle development and steroidogenesis through PPARG pathways. Treatment with GW1929, a selective PPARG agonist, restored inhibition of FSH-induced follicle development and steroidogenesis by TNF, whereas treatment with GW9662, a selective PPARG antagonist, canceled the restorative effects of bezafibrate. Collectively, the results in this study suggest that bezafibrate may directly exhibit a restorative effect on the inhibition of ovarian follicle development and steroidogenesis by TNF through the PPARG pathway.