Fenofibrate Treatment Research Articles

Molecular Cloning, Characterization, and Expression Regulation of Acyl-CoA Synthetase 6 Gene and Promoter in Common Carp Cyprinus carpio.

Omega-3 long chain polyunsaturated fatty acids (n-3 LC-PUFA), particularly docosahexaenoic acids (22:6n-3, DHA), have positive effects on multiple biologic and pathologic processes. Fish are the major dietary source of n-3 LC-PUFA for humans. Growing evidence supports acyl-coenzyme A (acyl-CoA) synthetase 6 (acsl6) being involved in cellular DHA uptake and lipogenesis in mammals, while its molecular function and regulatory mechanism remain unknown in fish. The present study focused on investigating the molecular characterization and transcription regulation of the acsl6 gene in the freshwater teleost common carp (Cyprinus carpio). First, the full length of acsl6 cDNA contained a coding region of 2148 bp for 715 amino acids, which possessed all characteristic features of the acyl-CoA synthetase (ACSL) family. Its mRNA expression was the highest in the brain, followed by in the heart, liver, kidney, muscle, and eyes, but little expression was detected in the ovary and gills. Additionally, a candidate acsl6 promoter region of 2058 bp was cloned, and the sequence from −758 bp to −198 bp was determined as core a promoter by equal progressive deletion and electrophoretic mobility shift assay. The binding sites for important transcription factors (TFs), including stimulatory protein 1 (SP1), CCAAT enhancer-binding protein (C/EBPα), sterol-regulatory element binding protein 1c (SREBP1c), peroxisome proliferator activated receptor α (PPARα), and PPARγ were identified in the core promoter by site-directed mutation and functional assays. Furthermore, the intraperitoneal injection of PPARγ agonists (balaglitazone) increased the expression of acsl6 mRNA, coupling with an increased proportion of DHA in the muscle, while opposite results were obtained in the injection of the SREBP1c antagonist (betulin). However, the expression of acsl6 and DHA content in muscle were largely unchanged by PPARα agonist (fenofibrate) treatment. These results indicated that acsl6 may play an important role for the muscular DHA uptake and deposition in common carp, and PPARγ and SREBP-1c are the potential TFs involved in the transcriptional regulation of acsl6 gene. To our knowledge, this is the first report of the characterization of acsl6 gene and its promoter in teleosts.

Alterations in plasma triglycerides and ceramides: links with cardiac function in humans with type 2 diabetes

Cardiac dysfunction in T2D is associated with excessive FA uptake, oxidation, and generation of toxic lipid species by the heart. It is not known whether decreasing lipid delivery to the heart can effect improvement in cardiac function in humans with T2D. Thus, our objective was to test the hypothesis that lowering lipid delivery to the heart would result in evidence of decreased "lipotoxicity," improved cardiac function, and salutary effects on plasma biomarkers of cardiovascular risk. Thus, we performed a double-blind randomized placebo-controlled parallel design study of the effects of 12 weeks of fenofibrate-induced lipid lowering on cardiac function, inflammation, and oxidation biomarkers, and on the ratio of two plasma ceramides, Cer d18:1 (4E) (1OH, 3OH)/24:0 and Cer d18:1 (4E) (1OH, 3OH)/16:0 (i.e., "C24:0/C16:0"), which is associated with decreased risk of cardiac dysfunction and heart failure. Fenofibrate lowered plasma TG and cholesterol but did not improve heart systolic or diastolic function. Fenofibrate treatment lowered the plasma C24:0/C16:0 ceramide ratio and minimally altered oxidative stress markers but did not alter measures of inflammation. Overall, plasma TG lowering correlated with improvement of cardiac relaxation (diastolic function) as measured by tissue Doppler-derived parameter e'. Moreover, lowering the plasma C24:0/C16:0 ceramide ratio was correlated with worse diastolic function. These findings indicate that fenofibrate treatment per se is not sufficient to effect changes in cardiac function; however, decreases in plasma TG may be linked to improved diastolic function. In contrast, decreases in plasma C24:0/C16:0 are linked with worsening cardiac function.

Fenofibrate ameliorates testicular damage in rats with streptozotocin-induced type 1 diabetes: role of HO-1 and p38 MAPK.

Since diabetes mellitus type-1 (DM-1) induces testicular oxidative and inflammatory damage with finally an ultimate male infertility, and as fenofibrate (FEN) plays an important antioxidant and anti-inflammatory role, the aim of the present study was to investigate the effects of FEN on diabetes-induced reproductive damage and clarifying the underlying related mechanisms. DM-1 was induced in male Wistar rats by a single intraperitoneal injection of streptozotocin (50mg/kg). FEN (100mg/kg/day, orally) was administrated to diabetic rats for 4weeks. Testicular damage was detected by estimation of both testicular and body weights, assessment of serum testosterone, testicular oxidative stress parameters (malondialdehyde and nitric oxide levels) and testicular oxidant defenses (reduced glutathione, superoxide dismutase and hemeoxygenase-1). Expressions of the inflammatory markers (inducible nitric oxide synthase, p38mitogen-activated protein kinase (MAPK), tumor necrosis factor alpha, interleukin-6 and apoptotic marker (caspase-3) were evaluated in testicular tissue. Our results were confirmed by histopathological examination of testicular tissues. Diabetic testicular damage was proved by both biochemical and histopathological examinations. FEN treatment reversed diabetic testicular damage; normalized the serum testosterone level, improved anti-oxidative capacity, ameliorated the pro-inflammatory cytokine expression in testicular tissue with the down regulation of p38 MAPK mediated-testicular apoptosis. FEN treatment exerted a protective effect against streptozotocin-induced diabetic reproductive dysfunction not only through its powerful antioxidant and hypoglycemic effects, but also through its anti-inflammatory and anti-apoptotic effect via down-regulation of testicular p38 MAPK expression in diabetic rats.

Fenofibrate decreased microalbuminuria in the type 2 diabetes patients with hypertriglyceridemia

BackgroundThis study was to research the efficacy of fenofibrate in the treatment of microalbuminuria in the patients with type 2 diabetes mellitus (T2DM) and hypertriglyceridemia.MethodsType 2 diabetic patients (56) with microalbuminuria and hypertriglyceridemia aged 30 to 75 were randomly divided into the fenofibrate treatment group(n = 28) and the control group (n = 28) for 180 days. Urinary microalbumin /creatinine ratio (UACR) and other metabolic parameters were compared at baseline, during treatment and after treatment.ResultsAfter 180 days, the reduction of level of fasting blood glucose (FBG) and glycosylated hemoglobin (HbA1c) between two groups showed no difference. In the treatment group, uric acid (UA) (296.42 ± 56.41 vs 372.46 ± 72.78), triglyceride (TG) [1.51(1.17, 2.06) vs 3.04(2.21, 3.29)], and UACR [36.45 (15.78,102.41) vs 129.00 (53.00, 226.25)] were significantly decreased compared with the baseline. The high-density lipoprotein cholesterol (HDL-C) levels were significantly increased (1.22 ± 0.26 vs 1.09 ± 0.24) compared with the baseline. The decrease in UACR [− 44.05(− 179.47, − 12.16) vs − 8.15(− 59.69, 41.94)]in treatment group was significantly higher compared with the control group. The decrease in UACR was positively associated with the decreases in TG (r = 0.447, P = 0.042) and UA (r = 0.478, P = 0.024) after fenofibrate treatment.ConclusionIn the patients with hypertriglyceridemia and type 2 diabetes mellitus, fenofibrate can improve microalbuminuria and do not increase the deterioration of glomerular filtration rate.Trial registrationClinicalTrials.gov identifier: NCT02314533, 2014.12.9

Uric acid predicts long-term cardiovascular risk in type 2 diabetes but does not mediate the benefits of fenofibrate: The FIELD study.

To explore the relationship between baseline uric acid (UA) levels and long-term cardiovascular events in adults with type 2 diabetes (T2D) and to determine whether the cardioprotective effects of fenofibrate are partly mediated through its UA-lowering effects. Data from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial were utilized, comprising 9795 adults with T2D randomly allocated to treatment with fenofibrate or matching placebo. Plasma UA was measured before and after a 6-week, active fenofibrate run-in phase in all participants. Cox proportional hazards models were used to explore the relationships between baseline UA, pre-to-post run-in reductions in UA and long-term cardiovascular outcomes. Mean baseline plasma UA was 0.33 mmol/L (SD 0.08). Baseline UA was a significant predictor of long-term cardiovascular events, with every 0.1 mmol/L higher UA conferring a 21% increase in event rate (HR 1.21, 95% CI 1.13-1.29, P < .001). This remained significant after adjustment for treatment allocation, cardiovascular risk factors and renal function. The extent of UA reduction during fenofibrate run-in was also a significant predictor of long-term cardiovascular events, with every 0.1 mmol/L greater reduction conferring a 14% lower long-term risk (HR 0.86, 95% CI 0.76-0.97, P = .015). This effect was not modified by treatment allocation (Pinteraction = .77). UA is a strong independent predictor of long-term cardiovascular risk in adults with T2D. Although greater reduction in UA on fenofibrate is predictive of lower cardiovascular risk, this does not appear to mediate the cardioprotective effects of fenofibrate.

Design and rationale of a randomized control trial testing the effectiveness of combined therapy with STAtin plus FENOfibrate and statin alone in non-diabetic, combined dyslipidemia patients with non-intervened intermediate coronary artery disease - STAFENO study

BackgroundDespite the chronicled success of low-density lipoprotein cholesterol (LDLc)-lowering statin therapy, substantial residual cardiovascular (CV) disease risk remains a problem worldwide, highlighting the need to for combination therapies targeting non-LDLc factors, such as with fenofibrate.Methods/designThe STAFENO trial is a prospective, randomized, open-label, multi-center trial to compare the effect of statin plus fenofibrate with statin alone on the reduction and stabilization of plaque in non-diabetic, combined dyslipidemia patients with non-intervened, intermediate coronary artery disease (CAD) using virtual histology-intravascular ultrasound at 12 months. A total of 106 eligible patients are planned to be randomized to receive either a combination therapy (rosuvastatin 10 mg plus fenofibrate 160 mg/day) or monotherapy (rosuvastatin 10 mg/day) for 12 months. The primary endpoint of this study is the percentage change in the necrotic core volume. Secondary endpoints include changes in tissue characteristics and 1-year major CV events, including all-cause mortality, CV mortality, nonfatal myocardial infarction, stroke, and revascularization of the intervened and non-intervened lesions.DiscussionThe STAFENO trial will address whether combination treatment of statin and fenofibrate has an additive beneficial effect compared to statin alone on the reduction and stabilization of plaque and CV events in non-diabetic, combined dyslipidemia patients with non-intervened intermediate CAD.Trial registrationClinicalTrials.gov, NCT02232360. Registered 9 February 2014.https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0004ULE&selectaction=Edit&uid=U00023SZ&ts=2&cx=juppd2

Pathogenic Role of PPARα Downregulation in Corneal Nerve Degeneration and Impaired Corneal Sensitivity in Diabetes.

The purpose of this study was to investigate the protective role of peroxisome proliferator–activated receptor α (PPARα) against diabetic keratopathy and corneal neuropathy. Corneal samples were obtained from human donors with and without diabetes. Streptozotocin-induced diabetic rats and mice were orally treated with PPARα agonist fenofibrate. As shown by immunohistochemistry and Western blotting, PPARα was downregulated in the corneas of humans with diabetes and diabetic rats. Immunostaining of β-III tubulin demonstrated that corneal nerve fiber metrics were decreased significantly in diabetic rats and mice, which were partially prevented by fenofibrate treatment. As evaluated using a Cochet-Bonnet aesthesiometer, corneal sensitivity was significantly decreased in diabetic mice, which was prevented by fenofibrate. PPARα−/− mice displayed progressive decreases in the corneal nerve fiber density. Consistently, corneal sensitivity was decreased in PPARα−/− mice relative to wild-type mice by 21 months of age. Diabetic mice showed increased incidence of spontaneous corneal epithelial lesion, which was prevented by fenofibrate while exacerbated by PPARα knockout. Western blot analysis revealed significantly altered neurotrophic factor levels in diabetic rat corneas, which were partially restored by fenofibrate treatment. These results indicate that PPARα protects the corneal nerve from degeneration induced by diabetes, and PPARα agonists have therapeutic potential in the treatment of diabetic keratopathy.

Keratocytes promote corneal neovascularization through VEGFr3 induced by PPARα-inhibition

As the peroxisome proliferator – activated receptor alpha (PPARα) agonist, fenofibrate has been widely used to be a good lipid-regulating drug in the clinical application. In this study, we investigated the mechanism by which keratocytes inhibit the corneal neovascularization (CNV) through PPARα - activation. To do this, the CNV model was established by alkali burn, followed by being divided into three groups including control, fenofibrate and vehicle group. The expression of VEGFr3, MMP13 and PPARα in corneas of normal mouse and alkali-burned mouse was determined via quantitative RT- PCR (qRT-PCR) and Western blot analysis (WB). The CNV area was observed under a slit lamp microscope. The location of PPARα expression in the corneas was determined via immunohistochemistry. In cultured primary keratocytes, the effect of fenofibrate on PPARα, VEGFr3 and MMP13 expression was determined by qRT-PCR and WB. Besides, PPARα knockout (PPARα−/−) mouse CNV and keratocytes model were established to further confirm the effect of PPARα on VEGFr3 and MMP13 expression. We found that PPARα was expressed in epithelium, stroma and endothelium of the normal cornea, however, with relatively low level in the corneal stroma. Meanwhile, its expression was decreased markedly in the cornea during the stage of CNV formation. After treatment of fenofibrate, PPARα expression was promoted and the expression of VEGFr3 and MMP13 was inhibited in both CNV mice model and primary keratocytes, and CNV areas were decreased in CNV mice model. However, the results in PPARα−/− CNV and keratocytes model were opposite. Our results suggest that keratocytes could promote the expression of VEGFr3 and MMP13, and CNV formation through PPARα downregulation.

Fenofibrate Facilitates Post-Active Tuberculosis Infection in Macrophages and is Associated with Higher Mortality in Patients under Long-Term Treatment.

Background: Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that infects and persists in macrophages. This study aimed to investigate the effects of long-term fenofibrate treatment in patients with tuberculosis (TB), and the intracellular viability of Mtb in human macrophages. Methods: Epidemiological data from the National Health Insurance Research Database of Taiwan were used to present outcomes of TB patients treated with fenofibrate. In the laboratory, we assessed Mtb infection in macrophages treated with or without fenofibrate. Mtb growth, lipid accumulation in macrophages, and expression of transcriptional genes were examined. Results: During 11 years of follow-up, TB patients treated with fenofibrate presented a higher risk of mortality. Longer duration of fenofibrate use was associated with a significantly higher risk of mortality. Treatment with fenofibrate significantly increased the number of bacilli in human macrophages in vitro. Fenofibrate did not reduce, but induced an increasing trend in the intracellular lipid content of macrophages. In addition, dormant genes of Mtb, icl1, tgs1, and devR, were markedly upregulated in response to fenofibrate treatment. Our results suggest that fenofibrate may facilitate intracellular Mtb persistence. Conclusions: Our data shows that long-term treatment with fenofibrate in TB patients is associated with a higher mortality. The underlying mechanisms may partly be explained by the upregulation of Mtb genes involved in lipid metabolism, enhanced intracellular growth of Mtb, and the ability of Mtb to sustain a nutrient-rich reservoir in human macrophages, observed during treatment with fenofibrate.

PPARA Polymorphism Influences the Cardiovascular Benefit of Fenofibrate in Type 2 Diabetes: Findings From ACCORD-Lipid.

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34–0.72), whereas no benefit was observed for other genotypes (Pinteraction = 3.7 × 10−4). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N = 585, P = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N = 3059, P = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11—a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.

Pemafibrate Tends to have Better Efficacy in Treating Dyslipidemia than Fenofibrate.

To compare the efficacy of pemafibrate (PF) and fenofibrate (FF) in treating dyslipidemia. A comprehensive search was performed on the public database to identify relevant randomized controlled trials (RCTs), which compared the effects of PF and FF treatment in lipid parameters among patients with dyslipidemia. Mean difference (MD) and 95% confidence intervals (CI) were pooled for continuous outcomes, whereas odds ratio (OR) and 95% CI were calculated for dichotomous outcomes. Three RCTs were included with a total of 744 patients (PF=547 and FF=197). Compared with the FF group (100mg/day), PF group (0.05 to 0.4mg/day) had a better effect on reducing triglycerides (TGs) (MD, -8.66; 95%CI, -10.91 to -6.41), very low-density lipoprotein cholesterol (VLDL-C, MD, -12.19; 95%CI, -15.37 to - 9.01), remnant lipoprotein cholesterol (MD, -13.16; 95%CI, -17.62 to -8.69), apolipoprotein-B48 (ApoB48, MD, -12.74; 95%CI, -17.71 to -7.76) and ApoCIII (MD, -6.25; 95%CI, -11.85 to -0.64). Although a slightly LDL-Cincreasing effect was found in PF-treated group (MD, 3.10; 95%CI, -0.12 to 6.09), the levels of HDL-C (MD, 3.59; 95%CI, 1.65 to 5.53) and ApoAI (MD, 1.60; 95%CI, 0.38 to 2.82) were significantly increased in the PF group. However, no significant difference was found in the level of total cholesterol (MD, 0.01; 95%CI, -1.37 to - 1.39), non-HDL-C (MD, -0.06; 95%CI, -1.75 to 1.63), ApoB (MD, 0.39; 95%CI, -1.37 to 2.15) and ApoAII (MD, 3.31; 95%CI, -1.66 to 8.29) between the two groups. In addition, the incidence of total adverse events (OR, 0.68; 95%CI, 0.53 to 0.86) and adverse drug reactions (OR, 0.36; 95%CI, 0.24 to 0.54) was lower in the PF group than that in the FF group. Pemafibrate tends to have better efficacy in treating dyslipidemia than fenofibrate.

The Role of Akt2 in the Protective Effect of Fenofibrate against Diabetic Nephropathy.

Fenofibrate (FF) protects against diabetic nephropathy (DN) in type 1 diabetic (T1D) mice by upregulating the expression of fibroblast growth factor 21 (FGF21), leading to the activation of the Akt-mediated Nrf2 antioxidant pathways. Here, we examined which isoforms of Akt contribute to FF activation of FGF21-mediated renal protection by examining the phosphorylation and expression of three isoforms, Akt1, Akt2, and Akt3. T1D induced by a single intraperitoneal dose of streptozotocin (STZ) resulted in reduced phosphorylation of one isoform, Akt2, but FF treatment increased renal Akt2 phosphorylation in these and normal mice, suggesting a potential and specific role for renal Akt2 in FF protection against T1D. This was further confirmed using in vitro cultured HK-2 human kidney tubule cells exposed to high glucose (HG) with siRNA silencing of the Akt2 gene and STZ-induced diabetic Akt2-knockout mice with and without 3-month FF treatment. In normal HK-2 cells exposed to HG for 24 hours, FF completely prevented cell death, reduced total Akt expression and glycogen synthase kinase (GSK)-3β phosphorylation, increased nuclear accumulation of Fyn, and reduced nuclear Nrf2 levels. These positive effects of FF were partially abolished by silencing Akt2 expression. Similarly, FF abolished T1D-induced renal oxidative stress, inflammation, and renal dysfunction in wild-type mice, but was only partially effective in Akt2-KO mice. Furthermore, FF treatment stimulated phosphorylation of AMPKα, an important lipid metabolism mediator, which in parallel with Akt2 plays an important role in FF protection against HG-induced HK-2 cells oxidative stress and damage. These results suggest that FF protects against DN through FGF21 to activate both Akt2/GSK-3β/Fyn/Nrf2 antioxidants and the AMPK pathway. Therefore, FF could be repurposed for the prevention of DN in T1D patients.

Red cabbage (Brassica oleracea L.) extract reverses lipid oxidative stress in rats.

Red cabbage (Brassica oleracea L. var. capitata f. rubra DC.) extract has been demonstrated hypolipidemic and antioxidant capacity. Herein, we investigated the effect of red cabbage aqueous extract (RC) or fenofibrate (FF) in oxidative stress induced by Triton WR-1339 in rats. The antioxidant capacity was evaluated through the superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities and, thiobarbituric reactive species (TBARS) and protein carbonyl (PC) levels in erythrocytes, liver, kidneys, cerebral cortex and hippocampus of male rats. The alterations promoted by Triton WR-1339 in enzymatic antioxidant defense in the liver, kidneys and hippocampus were reversed by RC or FF treatments. The TBARS and PC levels increased in the liver, cerebral cortex and hippocampus of hyperlipidemic rats were decreased by the treatments with RC or FF. These findings demonstrated that RC is a potential therapy to treat diseases not only involving dyslipidemic condition but also oxidative stress.

Fenofibrate-induced renal dysfunction, yes or no?

In the treatment process of hypertriglyceridemia and diabetic nephropathy in type 2 diabetes, fenofibrate (FEN) is a well-known medication. FEN is from fibrate class drugs that using orally; however, as a side effect, it is associated with serum creatinine level increasing. The aim of this review was to determine the real effect of FEN therapy on renal functions based on both experimental and clinical studies. For this review, using the keywords of “fenofibrate” and “renal” and “function,” a variety of sources of information banks, including PubMed, Google Scholar, and Scopus, were used, and the published articles were considered and interpreted. Followed by searching in databases, 45 articles were collected. After screening these articles, based on the study source, they were devided into two parts: 23 articles on animal experiments and 22 articles clinical experiments. Based on this information, it seems that the protective mechanism of FEN is related to vascular endothelial functions. The increased creatinine by FEN is related to different sensitivities to FEN effects caused by a polymorphism in different patients. In patients with normal renal function, follow-up of serum creatinine would be necessary after FEN, but the discontinuation of FEN is not recommended. In addition, in diabetic patients with hypertriglyceridemia, FEN treatment would be suggested for protecting the kidney from diabetes-induced renal injury.

Impaired Peroxisomal Fitness in Obese Mice, a Vicious Cycle Exacerbating Adipocyte Dysfunction via Oxidative Stress.

Aims: Peroxisome is a critical organelle for fatty acid oxidation (FAO) and metabolism of reactive oxygen species (ROS). Increased oxidative stress in adipose tissue contributes to the development of insulin resistance and metabolic syndrome in obesity. This study aimed to investigate the role of peroxisomal fitness in maintaining adipocyte function, which has been under-rated in the obesity research area. Results: Reduced peroxisomal gene expressions in white adipose tissue (WAT) of obese mice suggested a close correlation between peroxisomes and obesity. Peroxisomal biogenesis factor 5 siRNA increased cellular ROS and inflammatory mediators in 3T3-L1 adipocytes. On the contrary, hydrogen peroxide or tumor necrosis factor-α treatment significantly decreased biogenesis- and function-related peroxisomal proteins, suggesting a positive feedback loop of ROS/inflammation and peroxisomal dysfunction. Correspondingly, catalase (a major peroxisomal antioxidant)-knockout mice fed with high-fat diet (HFD) exhibited suppressed peroxisomal proteins along with increased oxidative stress and accelerated obesity. In response to fenofibrate (a peroxisomal proliferator) treatment, WAT of HFD-fed wild-type mice showed not only increases in peroxisomal biogenesis and FAO but also attenuated features of adipocyte dysfunction and obesity. However, these results were not observed in peroxisome proliferator-activated receptor-alpha null obese mice. Innovation: Impaired peroxisomal fitness enhanced oxidative stress and inflammation in adipocytes, which exacerbates obesity. Conclusion: Adipose tissue peroxisomal homeostasis plays an important role in attenuating the features of obesity, and it can be a potential therapeutic target of obesity.

Absolute Quantification of Apolipoproteins Following Treatment with Omega-3 Carboxylic Acids and Fenofibrate Using a High Precision Stable Isotope-labeled Recombinant Protein Fragments Based SRM Assay

Stable isotope-labeled standard (SIS) peptides are used as internal standards in targeted proteomics to provide robust protein quantification, which is required in clinical settings. However, SIS peptides are typically added post trypsin digestion and, as the digestion efficiency can vary significantly between peptides within a protein, the accuracy and precision of the assay may be compromised. These drawbacks can be remedied by a new class of internal standards introduced by the Human Protein Atlas project, which are based on SIS recombinant protein fragments called SIS PrESTs. SIS PrESTs are added initially to the sample and SIS peptides are released on trypsin digestion. The SIS PrEST technology is promising for absolute quantification of protein biomarkers but has not previously been evaluated in a clinical setting. An automated and scalable solid phase extraction workflow for desalting and enrichment of plasma digests was established enabling simultaneous preparation of up to 96 samples. Robust high-precision quantification of 13 apolipoproteins was achieved using a novel multiplex SIS PrEST-based LC-SRM/MS Tier 2 assay in non-depleted human plasma. The assay exhibited inter-day coefficients of variation between 1.5% and 14.5% (median = 3.5%) and was subsequently used to investigate the effects of omega-3 carboxylic acids (OM3-CA) and fenofibrate on these 13 apolipoproteins in human plasma samples from a randomized placebo-controlled trial, EFFECT I (NCT02354976). No significant changes were observed in the OM3-CA arm, whereas treatment with fenofibrate significantly increased apoAII and reduced apoB, apoCI, apoE and apoCIV levels. The reduction in apoCIV following fenofibrate treatment is a novel finding. The study demonstrates that SIS PrESTs can facilitate the generation of robust multiplexed biomarker Tier 2 assays for absolute quantification of proteins in clinical studies.

Pemafibrate Prevents Retinal Pathological Neovascularization by Increasing FGF21 Level in a Murine Oxygen-Induced Retinopathy Model.

Large-scale clinical trials, such as the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) studies, have shown that the administration of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, suppresses the progression of diabetic retinopathy. In this paper, we reveal a therapeutic effect of a selective PPARα modulator (SPPARMα), pemafibrate, against pathological angiogenesis in murine models of retinopathy. Oxygen-induced retinopathy (OIR) was induced in C57BL/6J mice by exposure to 85% oxygen from postnatal day eight (P8) for 72 h. Vehicle, pemafibrate or fenofibrate was administrated by oral gavage from P12 to P16 daily. Administration of pemafibrate, but not fenofibrate, significantly reduced pathological angiogenesis in OIR. After oral pemafibrate administration, expression levels of downstream PPARα targets such as acyl-CoA oxidase 1 (Acox1), fatty acid binding protein 4 (Fabp4), and fibroblast growth factor 21 (Fgf21) were significantly increased in the liver but not in the retina. A significant increase in plasma FGF21 and reduced retinal hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (Vegfa) were also observed after this treatment. In an in vitro HIF-luciferase assay, a long-acting FGF21 analogue, but not pemafibrate, suppressed HIF activity. These data indicate that SPPARMα pemafibrate administration may prevent retinal pathological neovascularization by upregulating FGF21 in the liver.

Fenofibrate Reverses Dysfunction of EPCs Caused by Chronic Heart Failure.

The enhanced activity of endothelial progenitor cells (EPCs) by AMP-activated protein kinase (AMPK) agonists might explain the reversal of chronic heart failure (CHF)-mediated endothelial dysfunction. We studied baseline circulating EPC numbers in patients with heart failure and clarified the effect of fenofibrate on both circulating angiogenic cell (CAC) and late EPC activity. The numbers of circulating EPCs in CHF patients were quantified by flow cytometry. Blood-derived mononuclear cells were cultured, and CAC and late EPC functions, including fibronectin adhesion, tube formation, and migration, were evaluated. We focused on the effect of fenofibrate, an AMPK agonist, on EPC function and Akt/eNOS cascade activation in vitro. The number of circulating EPCs (CD34+/KDR+) was significantly lower in CHF patients (ischemic cardiomyopathy (ICMP): 0.07%, dilated cardiomyopathy (DCMP): 0.068%; p < 0.05) than in healthy subjects (0.102% of the gating region). In CACs, fibronectin adhesion function was reversed by fenofibrate treatment (p < 0.05). Similar results were also found for tube formation and migration in late EPCs, which were significantly improved by fenofibrate in an AMPK-dependent manner (p < 0.05), suggesting that fenofibrate reversed CACs and late EPC dysfunction in CHF patients. The present findings reveal the potential application of the AMPK agonist fenofibrate to reverse endothelial dysfunction in CHF patients.

Effect of fenofibrate on diabetic retinopathy in rats via SIRT1/NF-κB signaling pathway.

To explore the influence of fenofibrate on the diabetic retinopathy (DR) in rats via the sirtuin1 (SIRT1)/nuclear factor-κB (NF-κB) signaling pathway. A total of 30 SD rats were divided into group A (DR group), group B (fenofibrate treatment group) and group C (Healthy group). Rats in group A were intraperitoneally injected with 50 mg/kg streptozotocin (STZ) for 5 days without feeding. After fasting for 2 days, blood was drawn from the tail veins of the rats to measure blood glucose, and blood glucose ≥16.7 mmol/L represented that the model was eligible. Those in group B were injected with STZ and nourished with the mixed feed containing fenofibrate (10 mg/kg). Those in group C were intraperitoneally injected with normal saline and set as negative control group. The retinal structure of rats in the three groups was observed via immunohistochemical staining, and the apoptosis of retinal ganglion cells (RGCs) was evaluated via terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Moreover, the protein expressions of Sirtuin1 (SIRT1) and NF-κB were detected using immunofluorescence assay and Western blotting. According to the immunohistochemical staining results, rats in group C had intact retinal nuclear layer tissues without phenomena such as fracture, disorderly arrangement, blur structures, and nerve fiber layer edema. Those in group A exhibited fracture of retinal nuclear layer tissues, disorderly arranged cells, blur retinal structures at all layers, and a quite evident nerve fiber layer edema. Compared to that in group A, the nerve fiber layer edema in group B was significantly improved. The TUNEL assay results revealed that compared to normal rats in group C, those in group A and group B had apoptotic RGCs. Additionally, the number of apoptotic cells was the largest in group A, and compared to that in group A, it was notably reduced in group B after treatment with fenofibrate. According to the immunofluorescence assay results, after being treated with fenofibrate, rats in group B showed a significantly lower protein expression level of NF-κB in the retina than in group A. Based on the Western blotting detection results, the protein expression level of NF-κB in group B was evidently lower than that in group A, and was the highest in group A and the lowest in group C. Compared to that in group C, the protein expression level of SIRT1 in group B was increased. Fenofibrate facilitates the expression of SIRT1 in the retinal tissues to reduce the NF-κB activity, thereby treating DR in rats.

New treatments/targets for primary biliary cholangitis.

SummaryPrimary biliary cholangitis (PBC) is an autoimmune, cholestatic, chronic liver disease that ultimately progresses towards cirrhosis and liver failure if untreated. While ursodeoxycholic acid has been established as standard of care for PBC in the last few decades, significant advances in second-line treatment options have recently been made and new therapeutic developments are currently under evaluation. The purpose of this article is to provide the clinician with an overview of the current treatment options and future opportunities for patients with PBC.