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Background: Heart failure (HF) is a serious and common condition affecting millions of people worldwide, with obesity being a major cause of metabolic disorders such as diabetes and cardiovascular disease. This study aimed to investigate the effects of fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, on the obese- and diabetes-related cardiomyopathy., Methods and Results: We used db/db mice and high fat diet-streptozotocin induced diabetic mice to investigate the underlying mechanisms of fenofibrate's beneficial effects on heart function. Fenofibrate reduced fibrosis, and lipid accumulation, and suppressed inflammatory and immunological responses in the heart via TNF signaling. In addition, we investigated the beneficial effects of fenofibrate on HF hospitalization. The Korean National Health Insurance database was used to identify 427,154 fenofibrate users and 427,154 non-users for comparison. During the 4.22-year follow-up, fenofibrate use significantly reduced the risk of HF hospitalization (hazard ratio, 0.907; 95% CI 0.824-0.998)., Conclusions: The findings suggest that fenofibrate may be a useful therapeutic agent for obesity- and diabetes-related cardiomyopathy., (© 2024. The Author(s).)

Diabetic wounds represent a common chronic condition, posing significant challenges in the treatment process due to bacterial infections, increased generation of reactive oxygen species (ROS) and exacerbated inflammation. Fenofibrate (FEN) is a clinical medication used for lipid regulation. In this study, it was utilized for the first time as an effective component of wound dressings for treating diabetic ulcers, exploring its novel applications further. Therefore, we prepared a polyvinyl alcohol/chitosan/FEN (PCF) hydrogel using a freeze-thaw method and conducted physicochemical characterization of the PCF hydrogel to further elucidate its biological functions. In vitro studies demonstrated that the PCF hydrogel exhibits excellent biocompatibility along with significant antimicrobial, pro-angiogenic, ROS-scavenging, and anti-inflammatory properties. Subsequent animal experiments indicated that the PCF hydrogel has the ability to promote blood vessel formation and collagen deposition. Additionally, the PCF hydrogel showed a significant inhibitory effect on the inflammatory response, as evidenced by the reductions in the levels of tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). These compelling findings accentuate the promising application of the PCF hydrogel in the treatment of diabetic wounds.

Fenofibrate, a PPAR-α agonist clinically used to lower serum lipid levels, reduces cardiac remodeling and improves cardiac function. However, its mechanism of action is not completely elucidated. In this study we examined the effect of fenofibrate on mitochondria in a rat model of renovascular hypertension, focusing on mediators controlling mitochondrial dynamics and autophagy. Rats with two-kidney one-clip (2K1C) hypertension were treated with fenofibrate 150 mg/kg/day (2K1C-FFB) or vehicle (2K1C-VEH) for 8 weeks. Systolic blood pressure and cardiac functional were in-vivo assessed, while cardiomyocyte size and protein expression of mediators of cardiac hypertrophy and mitochondrial dynamics were ex-vivo examined by histological and Western blot analyses. Fenofibrate treatment counteracted the development of hypertension and the increase of left ventricular mass, relative wall thickness and cross-sectional area of cardiomyocytes. Furthermore, fenofibrate re-balanced the expression Mfn2, Drp1 and Parkin, regulators of fusion, fission, mitophagy respectively. Regarding autophagy, the LC3-II/LC3-I ratio was increased in 2K1C-VEH and 2K1C-FFB, whereas the autophagy was increased only in 2K1C-FFB. In cultured H9C2 cardiomyoblasts, fenofibrate reversed the Ang II-induced mRNA up-regulation of hypertrophy markers Nppa and Myh7, accumulation of reactive oxygen species and depolarization of the mitochondrial membrane exerting protection mediated by up-regulation of the Uncoupling protein 2. Our results indicate that fenofibrate acts directly on cardiomyocytes and counteracts the pressure overload-induced cardiac maladaptive remodeling. This study reveals a so far hidden mechanism involving mitochondrial dynamics in the beneficial effects of fenofibrate, support its repurposing for the treatment of cardiac hypertrophy and provide new potential targets for its pharmacological function., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Luigi Sironi reports financial support was provided by University of Milan. Luigi Sironi reports a relationship with University of Milan that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Peroxisome proliferator-activated receptor-alpha (PPAR-α) and its exogenous activators (fibrates) promote autophagy. However, whether the deleterious effects of PPAR-α deficiency on doxorubicin (DOX)-induced podocytopathy are associated with reduced autophagy remains to be clarified. We investigated the mechanisms of PPAR-α in DOX-induced podocytopathy and tubular injury in PPAR-α knockout (PAKO) mice and in a murine podocyte cell line. DOX-treated PAKO mice showed higher serum levels of triglycerides and non-esterified fatty acids and more severe podocytopathy than DOX-treated wild-type mice, as evidenced by higher urinary levels of proteins and podocalyxin at 3 days to 2 weeks and higher blood urea nitrogen and serum creatinine levels at 4 weeks. Additionally, there was an increased accumulation of p62, a negative autophagy marker, in the glomerular and tubular regions in DOX-treated PAKO mice at Day 9. Moreover, DOX-treated PAKO mice showed more severe glomerulosclerosis and tubular damage and lower podocalyxin expression in the kidneys than DOX-treated control mice at 4 weeks. Furthermore, DOX treatment increased p-p53, an apoptosis marker, and cleaved the caspase-3 levels and induced apoptosis, which was ameliorated by fenofibrate, a PPAR-α activator. Fenofibrate further enhanced AMPK activation and autophagy under fed and fasting conditions. Conclusively, PPAR-α deficiency enhances DOX-induced podocytopathy, glomerulosclerosis, and tubular injury, possibly by reducing autophagic activity in mouse kidneys.

As research on in vitro cardiotoxicity assessment and cardiac disease modeling becomes more important, the demand for human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) is increasing. However, it has been reported that differentiated hPSC-CMs are in a physiologically immature state compared to in vivo adult CMs. Since immaturity of hPSC-CMs can lead to poor drug response and loss of acquired heart disease modeling, various approaches have been attempted to promote maturation of CMs. Here, we confirm that peroxisome proliferator-activated receptor alpha (PPARα), one of the representative mechanisms of CM metabolism and cardioprotective effect also affects maturation of CMs. To upregulate PPARα expression, we treated hPSC-CMs with fenofibrate (Feno), a PPARα agonist used in clinical hyperlipidemia treatment, and demonstrated that the structure, mitochondria-mediated metabolism, and electrophysiology-based functions of hPSC-CMs were all mature. Furthermore, as a result of multi electrode array (MEA)-based cardiotoxicity evaluation between control and Feno groups according to treatment with arrhythmia-inducing drugs, drug response was similar in a dose-dependent manner. However, main parameters such as field potential duration, beat period, and spike amplitude were different between the 2 groups. Overall, these results emphasize that applying matured hPSC-CMs to the field of preclinical cardiotoxicity evaluation, which has become an essential procedure for new drug development, is necessary., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: To investigate the neuroprotective effects of the SOD2 gene in cerebral ischemia reperfusion injury function and the underlying mechanisms in a mice model of middle cerebral artery ischemia reperfusion., Methods: SOD2 transgenic mice were engineered using transcription activator-like effector nucleases, and the genotype was identified using PCR after every three generations. Transgenic and C57BL/6J wild type mice were simultaneously subjected to the middle cerebral artery occlusion model., Results: SOD2 expression in the brain, heart, kidney, and skeletal muscle of transgenic mice was significantly higher than that in the wild type. Following ischemia reperfusion, the infarct volume of wild type mice decreased after treatment with fenofibrate compared to the CMC group. Infarction volume in SOD2 transgenic mice after CMC and fenofibrate treatment was significantly reduced. The recovery of cerebral blood flow in wild type mice treated with fenofibrate was significantly enhanced compared with that in the CMC group., Conclusions: The expression of SOD2 in transgenic mice was significantly higher than that in wild type mice, the neuroprotective role of fenofibrate depends on an increase in SOD2 expression.

Migraine, a debilitating neurological condition, significantly affects patients' quality of life. Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPAR-α) agonist approved for managing dyslipidemia, has shown promise in treating neurological disorders. Therefore, this study aims to investigate the protective effects of fenofibrate against nitroglycerin (NTG)-induced chronic migraine in rats. Migraine was induced in rats by administering five intermittent doses of NTG (10 mg/kg, i. p.) on days 1, 3, 5, 7, and 9. Rats were treated with either topiramate (80 mg/kg/day, p. o.), a standard drug, or fenofibrate (100 mg/kg/day, p. o.) from day 1-10. Fenofibrate significantly improved mechanical and thermal hypersensitivity, photophobia, and head grooming compared to topiramate. These effects were associated with reduced serum levels of nitric oxide (NO), calcitonin gene-related peptide (CGRP), and pituitary adenylate cyclase-activating polypeptide (PACAP). Furthermore, fenofibrate down-regulated c-Fos expression in the medulla and medullary pro-inflammatory cytokine contents. Additionally, fenofibrate attenuated NTG-induced histopathological changes in the trigeminal ganglia and trigeminal nucleus caudalis. These effects were associated with the inhibition of CGRP/p-CREB/purinergic 2X receptor 3 (P2X3) and nerve growth factor (NGF)/protein kinase C (PKC)/acid-sensing ion channel 3 (ASIC3) signaling pathways. This study demonstrates that fenofibrate attenuated NTG-induced migraine-like signs in rats. These effects were partially mediated through the inhibition of CGRP/p-CREB/P2X3 and NGF/PKC/ASIC3 signaling pathways. The present study supports the idea that fenofibrate could be an effective candidate for treating migraine headache without significant adverse effects. Future studies should explore its clinical applicability., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Findings from cardiovascular outcome trials suggest that fenofibrate therapy may reduce the progression of diabetic retinopathy., Methods: We recruited and followed adults with nonreferable diabetic retinopathy or maculopathy using the national Diabetic Eye Screening (DES) program in Scotland. We randomly assigned participants to receive 145-mg fenofibrate tablets or placebo (taken daily or, in those with impaired renal function, on alternate days). The primary outcome was a composite of developing referable diabetic retinopathy or maculopathy (based on Scotland's DES grading scheme) or treatment (intravitreal injection, retinal laser, vitrectomy) for retinopathy or maculopathy., Results: A total of 1151 participants were randomly assigned to treatment. During a median of 4.0 years, progression to referable diabetic retinopathy or maculopathy, or treatment thereof, occurred in 131 (22.7%) of 576 participants in the fenofibrate group and 168 (29.2%) of 575 in the placebo group (hazard ratio, 0.73; 95% confidence interval [CI], 0.58 to 0.91; P=0.006). In the fenofibrate group compared with the placebo group, the frequencies for any progression of retinopathy or maculopathy were 185 (32.1%) vs. 231 (40.2%); hazard ratio, 0.74; 95% CI, 0.61 to 0.90 and for the development of macular edema were 22 (3.8%) vs. 43 (7.5%); hazard ratio, 0.50; 95% CI, 0.30 to 0.84. Seventeen (3.0%) participants assigned fenofibrate and 28 (4.9%) assigned placebo were given treatment for retinopathy (hazard ratio, 0.58; 95% CI, 0.31 to 1.06). There was no effect on visual function, quality of life, or visual acuity. Trial-averaged estimated glomerular filtration rate was 7.9 (95% CI, 6.8 to 9.1) ml/min/1.73 m 2 lower in participants in the fenofibrate group compared with the placebo group. Serious adverse events occurred in 208 (36.1%) participants allocated fenofibrate and 204 (35.5%) participants allocated placebo., Conclusions: Fenofibrate reduced progression of diabetic retinopathy compared with placebo among participants with early retinal changes. (Funded by the National Institute for Health and Care Research; ClinicalTrials.gov number, NCT03439345; ISRCTN number, ISRCTN15073006.).

Diabetic corneal neuropathy (DCN) is a common diabetic ocular complication with limited treatment options. In this study, we investigated the effects of topical and oral fenofibrate, a peroxisome proliferator-activated receptor-α agonist, on the amelioration of DCN using diabetic mice (n = 120). Ocular surface assessments, corneal nerve and cell imaging analysis, tear proteomics and its associated biological pathways, immuno-histochemistry and western blot on PPARα expression, were studied before and 12 weeks after treatment. At 12 weeks, PPARα expression markedly restored after topical and oral fenofibrate. Topical fenofibrate significantly improved corneal nerve fibre density (CNFD) and tortuosity coefficient. Likewise, oral fenofibrate significantly improved CNFD. Both topical and oral forms significantly improved corneal sensitivity. Additionally, topical and oral fenofibrate significantly alleviated diabetic keratopathy, with fenofibrate eye drops demonstrating earlier therapeutic effects. Both topical and oral fenofibrate significantly increased corneal β-III tubulin expression. Topical fenofibrate reduced neuroinflammation by significantly increasing the levels of nerve growth factor and substance P. It also significantly increased β-III-tubulin and reduced CDC42 mRNA expression in trigeminal ganglions. Proteomic analysis showed that neurotrophin signalling and anti-inflammation reactions were significantly up-regulated after fenofibrate treatment, whether applied topically or orally. This study concluded that both topical and oral fenofibrate ameliorate DCN, while topical fenofibrate significantly reduces neuroinflammation., (© 2024. The Author(s).)

Background: The incidence of hypertriglyceridemic acute pancreatitis (HTG-AP) is increasing. Although the guideline defines the diagnostic criteria as triglyceride (TG) greater than 11.3 mmol/L, there is actually no specific threshold. Many people with hypertriglyceridemia (HTG) or obvious chyloid blood do not develop acute pancreatitis (AP)., Aims: To explore the role of HTG in the pathogenesis of AP., Methods: Thirty-six male SD rats were randomly assigned into normal control, AP, HTG, HTG-AP, low-dose fenofibrate and high-dose fenofibrate groups. Serum indices and cytokine levels in serum, and pathological changes in pancreatic tissues were observed. The expression levels of TLR4 and NF-κBp65 in pancreatic tissues were detected by immunohistochemistry and Western blot., Results: In normal rats, HTG alone did not induce AP. However, after establishing the HTG-AP model with Poloxam 407 and L-arginine, serum-free fatty acid and TG levels were positively correlated with the levels of lipase, amylase, IL-1β, IL-6, pancreatic inflammation scores, and the expressions of TLR4 and NF-κBp65 (all P < 0.001). Expressions of TLR4 and NF-κBp65 were significantly increased in the pancreatic tissues of HTG-AP rats. Fenofibrate effectively decreased TG levels in HTG-AP rats and reduced the expression of TLR4 and NF-κBp65 (all P < 0.001)., Conclusions: HTG does not directly cause AP, but rather increases the susceptibility to AP or aggravates the inflammatory response. It is more like a sensitizer of inflammation rather than an activator., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Autophagy is a cellular process that involves the fusion of autophagosomes and lysosomes to degrade damaged proteins or organelles. Triglycerides are hydrolyzed by autophagy, releasing fatty acids for energy through mitochondrial fatty acid oxidation (FAO). Inhibited mitochondrial FAO induces autophagy, establishing a crosstalk between lipid catabolism and autophagy. Peroxisome proliferator-activated receptor α (PPARα), a transcription factor, stimulates lipid catabolism genes, including fatty acid transport and mitochondrial FAO, while also inducing autophagy through transcriptional regulation of transcription factor EB (TFEB). Therefore, the study explores whether PPARα regulates autophagy through TFEB transcriptional control or mitochondrial FAO. In aquaculture, addressing liver lipid accumulation in fish is crucial. Investigating the link between lipid catabolism and autophagy is significant for devising lipid-lowering strategies and maintaining fish health. The present study investigated the impact of dietary fenofibrate and L-carnitine on autophagy by activating Pparα and enhancing FAO in Nile tilapia (Oreochromis niloticus), respectively. The dietary fenofibrate and L-carnitine reduced liver lipid content and enhanced ATP production, particularly fenofibrate. FAO enhancement by L-carnitine showed no changes in autophagic protein levels and autophagic flux. Moreover, fenofibrate-activated Pparα promoted the expression and nuclear translocation of Tfeb, upregulating autophagic initiation and lysosomal biogenesis genes. Pparα activation exhibited an increasing trend of LC3II protein at the basal autophagy and cumulative p62 protein trends after autophagy inhibition in zebrafish liver cells. These data show that Pparα activation-induced autophagic flux should be independent of lipid catabolism., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: The ongoing concern of the medical profession regarding chronic medication is related to increasing patient adherence and compliance to treatment and reducing medication side effects. In this respect, drugs represented by fixed-dose combinations of active substances within the same tablet have emerged. Such a principle can be extrapolated by following the potential beneficial effects that a chronic medication can have on chronic pathologies affecting different systems. Materials and Methods: The study included 48 female Albino Wistar rats, aged 16-18 months, which were divided into two groups: ovariectomized and non-ovariectomized rats. One batch of 12 non-ovariectomized rats received no treatment, becoming a control batch (NOVX-M). The ovariectomized (OVX) group was divided into 3 batches of 12 rats each: no treatment, control (OVX-M), fenofibrate-treated (OVX-F) and statin-treated (OVX-S) rats. At 12 weeks after ovariectomy, a femoral fracture occurred in the right hind limb of all animals included in the experiment To reveal the changes, at intervals of 2, 4, 6 and 8 weeks post-fracture, the proximal part of the femur was evaluated by NMR diffusiometry, which allows random motion of proton molecules expressed by self-diffusion coefficients, D , thus allowing analysis of the size and complexity of microscopic order cavities within biological structures, such as pores inside bones. Results: The effects of hypolipidemic medication in the absence of estrogen were evidenced, proving the beneficial effect that fenofibrate can have in preserving healthy tissue exposed to osteoporotic risk during the menopausal period. The effects of lipid-lowering medication are also influenced by the duration of administration. Conclusions: Osteoporosis and heart disease are two chronic pathologies that affect mainly female population in the second half of life, and proving the dual therapeutic potential of lipid-lowering medication may also have positive effects by increasing adherence and compliance to treatment.

Chagas disease, caused by Trypanosoma cruzi , stands as the primary cause of dilated cardiomyopathy in the Americas. Macrophages play a crucial role in the heart's response to infection. Given their functional and phenotypic adaptability, manipulating specific macrophage subsets could be vital in aiding essential cardiovascular functions including tissue repair and defense against infection. PPARα are ligand-dependent transcription factors involved in lipid metabolism and inflammation regulation. However, the role of fenofibrate, a PPARα ligand, in the activation profile of cardiac macrophages as well as its effect on the early inflammatory and fibrotic response in the heart remains unexplored. The present study demonstrates that fenofibrate significantly reduces not only the serum activity of tissue damage biomarker enzymes (LDH and GOT) but also the circulating proportions of pro-inflammatory monocytes (CD11b + LY6C high ). Furthermore, both CD11b + Ly6C low F4/80 high macrophages (MΦ) and recently differentiated CD11b + Ly6C high F4/80 high monocyte-derived macrophages (MdMΦ) shift toward a resolving phenotype (CD206 high ) in the hearts of fenofibrate-treated mice. This shift correlates with a reduction in fibrosis, inflammation, and restoration of ventricular function in the early stages of Chagas disease. These findings encourage the repositioning of fenofibrate as a potential ancillary immunotherapy adjunct to antiparasitic drugs, addressing inflammation to mitigate Chagas disease symptoms.

Purpose: Head and neck cancer (HNC) improvements are stagnant, even with advances in immunotherapy. Our previous clinical trial data show that altered fatty acid (FA) metabolism correlates with outcome. We hypothesized that pharmacologic and dietary modulation of FA catabolism will affect therapeutic efficacy., Experimental Design: We performed in vivo and in vitro experiments using PPARα agonism with fenofibrate (FF) or high oleic acid diets (OAD) with radiotherapy, generating metabolomic, proteomic, stable isotope tracing, extracellular flux analysis, and flow-cytometric data to investigate these alterations., Results: FF improved antitumor efficacy of high dose per fraction radiotherapy in HNC murine models, whereas the OAD reversed this effect. FF-treated mice on the control diet had evidence of increased FA catabolism. Stable isotope tracing showed less glycolytic utilization by ex vivo CD8+ T cells. Improved efficacy correlated with intratumoral alterations in eicosanoid metabolism and downregulated mTOR and CD36., Conclusions: Metabolic intervention with increased FA catabolism improves the efficacy of HNC therapy and enhances antitumoral immune response., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: Shen Shuai Ⅱ Recipe (SSR) is clinically used to treat chronic kidney diseases (CKDs) with remarkable efficacy and safety. In earlier research, we found the anti-inflammatory, antioxidant, and mitochondrial protective properties of SSR in hypoxic kidney injury model, which is closely related to its renal protection. Further work is needed to understand the underlying molecular mechanisms., Purpose: Further investigation of the mechanisms of action of SSR against renal interstitial fibrosis (RIF) building on previous research leads., Methods: Rats receiving CKD model surgery were given with Fenofibrate or SSR once a day for eight weeks. In vitro, the NRK-52E cells were treated with SSR in the presence or absence of 10 μM Sc75741, 0.5 μM PMA, or 1 μM fenofibrate under 1% O 2 . The effects of SSR on NF-κB/NLRP3 inflammatory cascade, secretion of pro-inflammatory cytokines, fatty acid oxidation (FAO), and renal tubular injury were determined by immunoblotting, luminex liquid suspension chip assay, transmission electron microscopy, and Oil red O staining. Next, we delivered PPARα-interfering sequences to kidney tissue and NRK-52E cells by adeno-associated virus (AAV) injection and siRNA transfection methods. Finally, we evaluated the effect of renal tubular cells on fibroblast activation by co-culture method., Results: SSR attenuated the release of IL-18, VEGF, and MCP1 cytokines, inhibited the activation of NF-κB/NLRP3 cascade, increased the PPARα, CPT-1α, CPT-2, ACADL, and MCAD protein expression, and improved the lipid accumulation. Further studies have demonstrated that one of the ways in which SSR suppresses the inflammatory response to protect renal tubular cells is through the restoration of PPARα-mediated FAO. In addition, by means of co-culture ways, the results demonstrated that SSR attenuated secretion of inflammatory mediators in NRK-52E cells by PPARα/NF-κB/NLRP3 pathway, thereby inhibiting renal fibroblast activation., Conclusion: SSR inhibits RIF by suppressing inflammatory response of hypoxia-exposed RTECs through PPARα-mediated FAO., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

We investigated the age-related effects of the lipid-lowering drug fenofibrate on renal stress-associated effectors. Young and old rats were fed standard chow with 0.1% or 0.5% fenofibrate. The kidney cortex tissue structure showed typical aging-related changes. In old rats, 0.1% fenofibrate reduced the thickening of basement membranes, but 0.5% fenofibrate exacerbated interstitial fibrosis. The PCR array for stress and toxicity-related targets showed that 0.1% fenofibrate mildly downregulated, whereas 0.5% upregulated multiple genes. In young rats, 0.1% fenofibrate increased some antioxidant genes' expression and decreased the immunoreactivity of oxidative stress marker 4-HNE. However, the activation of cellular antioxidant defenses was impaired in old rats. Fenofibrate modulated the expression of factors involved in hypoxia and osmotic stress signaling similarly in both age groups. Inflammatory response genes were variably modulated in the young rats, whereas old animals presented elevated expression of proinflammatory genes and TNFα immunoreactivity after 0.5% fenofibrate. In old rats, 0.1% fenofibrate more prominently than in young animals induced phospho-AMPK and PGC1α levels, and upregulated fatty acid oxidation genes. Our results show divergent effects of fenofibrate in young and old rat kidneys. The activation of multiple stress-associated effectors by high-dose fenofibrate in the aged kidney warrants caution when applying fenofibrate therapy to the elderly.

Multiple sclerosis (MS) is the most frequent inflammatory and demyelinating disease of the central nervous system (CNS). The underlying pathophysiology of MS is the destruction of myelin sheath by immune cells. The formation of myelin plaques, inflammation, and injury of neuronal myelin sheath characterizes its neuropathology. MS plaques are multiple focal regions of demyelination disseminated in the brain's white matter, spinal cords, deep grey matter, and cerebral cortex. Fenofibrate is a peroxisome proliferative activated receptor alpha (PPAR-α) that attenuates the inflammatory reactions in MS. Fenofibrate inhibits differentiation of Th17 by inhibiting the expression of pro-inflammatory signaling. According to these findings, this review intended to illuminate the mechanistic immunoinflammatory role of fenofibrate in mitigating MS neuropathology. In conclusion, fenofibrate can attenuate MS neuropathology by modulating different pathways, including oxidative stress, autophagy, mitochondrial dysfunction, inflammatory-signaling pathways, and neuroinflammation., (© 2024. The Author(s).)

Primary hepatic carcinoma (PHC) is a leading threat to cancer patients with few effective treatment strategies. OPN is found to be an oncogene in hepatocellular carcinoma (HCC) with potential as a treating target for PHC. Fenofibrate is a lipid-lowering drug with potential anti-tumor properties, which is claimed with suppressive effects on OPN expression. Our study proposes to explore the molecular mechanism of fenofibrate in inhibiting HCC. OPN was found extremely upregulated in 6 HCC cell lines, especially Hep3B cells. Hep3B and Huh7 cells were treated with 75 and 100 μM fenofibrate, while OPN-overexpressed Hep3B cells were treated with 100 μM fenofibrate. Decreased clone number, elevated apoptotic rate, reduced number of migrated cells, and shortened migration distance were observed in fenofibrate-treated Hep3B and Huh7 cells, which were markedly abolished by the overexpression of OPN. Furthermore, the facilitating effect against apoptosis and the inhibitory effect against migration of fenofibrate in Hep3B cells were abolished by 740 Y-P, an agonist of PI3K. Hep3B xenograft model was established, followed by treated with 100 mg/kg and 200 mg/kg fenofibrate, while OPN-overexpressed Hep3B xenograft was treated with 200 mg/kg fenofibrate. The tumor growth was repressed by fenofibrate, which was notably abolished by OPN overexpression. Furthermore, the inhibitory effect of fenofibrate on the PI3K/AKT/Twist pathway in Hep3B cells and Hep3B xenograft model was abrogated by OPN overexpression. Collectively, fenofibrate suppressed progression of hepatoma downregulating OPN through inhibiting the PI3K/AKT/Twist pathway., (© 2023. The Author(s).)

The recurrence and metastasis in breast cancer within 3 years after the chemotherapies or surgery leads to poor prognosis with approximately 1-year overall survival. Large-scale scanning research studies have shown that taking lipid-lowering drugs may assist to reduce the risk of death from many cancers, since cholesterol in lipid rafts are essential for maintain integral membrane structure and functional signaling regulation. In this study, we examined five lipid-lowering drugs: swertiamarin, gemfibrozil, clofibrate, bezafibrate, and fenofibrate in triple-negative breast cancer, which is the most migration-prone subtype. Using human and murine triple-negative breast cancer cell lines (Hs 578 t and 4 T1), we found that fenofibrate displays the highest potential in inhibiting the colony formation, wound healing, and transwell migration. We further discovered that fenofibrate reduces the activity of pro-metastatic enzymes, matrix metalloproteinases (MMP)-9 and MMP-2. In addition, epithelial markers including E-cadherin and Zonula occludens-1 are increased, whereas mesenchymal markers including Snail, Twist and α-smooth muscle actin are attenuated. Furthermore, we found that fenofibrate downregulates ubiquitin-dependent GDF-15 degradation, which leads to enhanced GDF-15 expression that inhibits cell migration. Besides, nuclear translocation of FOXO1 is also upregulated by fenofibrate, which may responsible for GDF-15 expression. In summary, fenofibrate with anti-cancer ability hinders TNBC from migration and invasion, and may be beneficial to repurposing use of fenofibrate., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Background: To comprehend the influences of fenofibrate on hepatic lipid accumulation and mitochondrial function-related signaling pathways in mice with non-alcoholic fatty liver disease (NAFLD) secondary to high-fat diets together with free fatty acids-influenced HepG2 cells model., Materials and Methods: A random allocation of male 6-week C57BL/6J mice into three groups was done, including controls, model (14 weeks of a high-fat diet), and fenofibrate [similar to the model one with administered 0.04 g/(kg.d) fenofibrate by gavage at 11 weeks for 4 weeks] groups, which contained 10 mice each. This study verified NAFLD pathogenesis via mitochondrial functions in hepatic pathological abnormalities, liver index and weight, body weight, serum biochemical indexes, oxidative stress indicators, mitochondrial function indexes, and related signaling pathways. The effect of fenofibrate intervention was investigated in NAFLD model mice. In vitro, four groups based on HepG2 cells were generated, including controls, the FFA model (1.5 mmol/L FFA incubation for 24 h), LV-PGC-1α intervention (similar to the FFA model one after PPARGC1A lentivirus transfection), and LV control intervention (similar to the FFA model one after negative control lentivirus transfection) groups. The study investigated the mechanism of PGC-1α related to lipid decomposition and mitochondrial biosynthesis by Oil red O staining, colorimetry and western blot., Results: In vivo experiments, a high-fat diet achieved remarkable changes regarding liver weight, liver index, serum biochemical indicators, oxidative stress indicators, liver pathological changes, mitochondrial function indicators, and body weight of the NAFLD model mice while fenofibrate improved the objective indicators. In the HepG2 cells model, the lipid accumulation increased significantly within the FFA model group, together with aggravated hepatocytic damage and boosted oxidative stress levels. Moreover, FFA induced excessive mitosis into fragmented in mitochondrial morphology, ATP content in cells decreased, mtDNA replication fold decreased, the expression of lipid decomposition protein PPARα reduced, mitochondrial biosynthesis related protein PGC-1α, NRF-1 and TFAM decreased. PGC-1α overexpression inhibited lipid deposition by improving mitochondrial biosynthesis and lipid decomposition., Conclusion: Fenofibrate up-regulated PPARα/PGC-1α signaling pathway, promoted mitochondrial β-oxidation, reduced oxidative stress damage and lipid accumulation of liver. PGC-1α overexpression enhanced mitochondrial biosynthesis and ATP production, and reduced HepG2 intracellular accumulation of lipids and oxidative stress., (© 2024. The Author(s).)

Impaired macroautophagy/autophagy flux has been implicated in the treatment of prostate cancer (PCa). However, the mechanism underlying autophagy dysregulation in PCa remains unknown. In the current study, we investigated the role of diacylglycerol acyltransferases 1 (DGAT1) and its potential effects on cellular energy homeostasis and autophagy flux in PCa. The results of immunohistochemical staining suggested that DGAT1 expression was positively corrected with tumor stage and node metastasis, indicating DGAT1 is an important factor involved in the development and progression of PCa. Furthermore, targeting DGAT1 remarkably inhibited cell proliferation in vitro and suppressed PCa growth in xenograft models by triggering severe oxidative stress and subsequently autophagy flux blockage. Mechanically, DGAT1 promoted PCa progression by maintaining cellular energy homeostasis, preserving mitochondrial function, protecting against reactive oxygen species, and subsequently promoting autophagy flux via regulating lipid droplet formation. Moreover, we found that fenofibrate exhibits as an upstream regulator of DGAT1. Fenofibrate performed its anti-PCa effect involved the aforementioned mechanisms, and partially dependent on the regulation of DGAT1. Collectively. These findings indicate that DGAT1 regulates PCa lipid droplets formation and is essential for PCa progression. Targeting DGAT1 might be a promising method to control the development and progression of PCa. Schematic representation of DGAT1 affects autophagy flux by regulating lipid homeostasis and maintaining mitochondrial function in prostate cancer (PCa). PCa is characterized up-regulation of DGAT1, leading to the translocation of free fatty acids into lipid droplets, thereby preventing PCa cell from lipotoxicity. Inhibition of DGAT1 suppresses growth of PCa by inducing oxidative stress and subsequently autophagy flux blockage. Further, the current results revealed that fenofibrate exhibits as an upstream regulator of DGAT1, and fenofibrate plays an anti-PCa role partially dependent on the regulation of DGAT1, suggesting a potential therapeutic approach to ameliorate this refractory tumor., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Aims: Alcoholic liver disease (ALD) can develop into cirrhosis and hepatocellular carcinoma but no specific drugs are available. Fenofibrate is therapeutically effective in ALD, however, the exact mechanism remains unknown. We explored the hub genes of ALD and the role of fenofibrate in ALD., Main Methods: The hub genes of ALD were screened by bioinformatics method, and their functional enrichment, signalling pathways, target genes and their correlation with immune microenvironment and pathogenic genes were analysed. We also analysed the binding affinity of fenofibrate to proteins of hub genes using molecular docking techniques, and the effects on hub gene expression, lipid deposition, oxidative stress and inflammation in the liver of National Institute on Alcohol Abuse and Alcoholism (NIAAA) model mice. The regulatory effects of fenofibrate on MOXD1 and PDZK1P1 were investigated after gene silencing of peroxisome proliferator-activated receptor-α (Ppar-α)., Key Findings: Hub genes identified, including monooxygenase DBH-like 1 (MOXD1), PDZK1-interacting protein 1 (PDZK1IP1) and solute carrier 51 β (SLC51B), are highly predictive for ALD. Hepatic MOXD1 and PDZK1IP1 expression was elevated in patients with ALD and NIAAA model mice, with no significant difference in SLC51B expression between the groups. Fenofibrate binds tightly to MOXD1 and PDZK1IP1, inhibits their hepatic expression independently of PPAR-α signalling, and ameliorates lipid deposition, oxidative stress and inflammatory responses in NIAAA model mice., Significance: MOXD1 and PDZK1IP1 are key genes in ALD progression; fenofibrate improves liver damage in NIAAA model mice by downregulating their expression. Our findings provide insight for improving diagnostic and therapeutic strategies for ALD., Competing Interests: Declaration of competing interest The authors declare no conflict of interest for this article., (Copyright © 2023. Published by Elsevier Inc.)

Diabetes mellitus (DM) is a common chronic metabolic disease in humans and household cats that is characterized by persistent hyperglycemia. DM is associated with dysfunction of the intestinal barrier. This barrier is comprised of an epithelial monolayer that contains a network of tight junctions that adjoin cells and regulate paracellular movement of water and solutes. The mechanisms driving DM-associated barrier dysfunction are multifaceted, and the direct effects of hyperglycemia on the epithelium are poorly understood. Preliminary data suggest that fenofibrate, An FDA-approved peroxisome proliferator-activated receptor-alpha (PPARα) agonist drug attenuates intestinal barrier dysfunction in dogs with experimentally-induced DM. We investigated the effects of hyperglycemia-like conditions and fenofibrate treatment on epithelial barrier function using feline intestinal organoids. We hypothesized that glucose treatment directly increases barrier permeability and alters tight junction morphology, and that fenofibrate administration can ameliorate these deleterious effects. We show that hyperglycemia-like conditions directly increase intestinal epithelial permeability, which is mitigated by fenofibrate. Moreover, increased permeability is caused by disruption of tight junctions, as evident by increased junctional tortuosity. Finally, we found that increased junctional tortuosity and barrier permeability in hyperglycemic conditions were associated with increased protein kinase C-α (PKCα) activity, and that fenofibrate treatment restored PKCα activity to baseline levels. We conclude that hyperglycemia directly induces barrier dysfunction by disrupting tight junction structure, a process that is mitigated by fenofibrate. We further propose that counteracting modulation of PKCα activation by increased intracellular glucose levels and fenofibrate is a key candidate regulatory pathway of tight junction structure and epithelial permeability., (© 2023. The Author(s).)

Maternal infections during pregnancy may increase the risk of psychiatric disorders in offspring. We recently demonstrated that activation of peroxisome proliferator-activate receptor-α (PPARα), with the clinically available agonist fenofibrate (FEN), attenuates the neurodevelopmental disturbances induced by maternal immune activation (MIA) in rat offspring. We hypothesized that fenofibrate might reduce MIA-induced cytokine imbalance using a MIA model based on the viral mimetic polyriboinosinic-polyribocytidilic acid [poly (I:C)]. By using the Bio-Plex Multiplex-Immunoassay-System, we measured cytokine/chemokine/growth factor levels in maternal serum and in the fetal brain of rats treated with fenofibrate, at 6 and 24 h after poly (I:C). We found that MIA induced time-dependent changes in the levels of several cytokines/chemokines/colony-stimulating factors (CSFs). Specifically, the maternal serum of the poly (I:C)/control (CTRL) group showed increased levels of (i) proinflammatory chemokine macrophage inflammatory protein 1-alpha (MIP-1α), (ii) tumor necrosis factor-alpha (TNF-α), the monocyte chemoattractant protein-1 (MCP-1), the macrophage (M-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Conversely, in the fetal brain of the poly (I:C)/CTRL group, interleukin 12p70 and MIP-1α levels were lower than in vehicle (veh)/CTRL group. Notably, MIP-1α, TNF-α, keratinocyte derived chemokine (GRO/KC), GM-CSF, and M-CSF levels were lower in the poly (I:C)/FEN than in poly (I:C)/CTRL rats, suggesting the protective role of the PPARα agonist. PPARα might represent a therapeutic target to attenuate MIA-induced inflammation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that might have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is a major liver disease subtype worldwide, is commonly associated with insulin resistance and obesity. NAFLD is characterized by an excessive hepatic lipid accumulation, as well as hepatic steatosis. Fenofibrate is a peroxisome proliferator-activated receptor α agonist widely used in clinical therapy to effectively ameliorate the development of NAFLD, but its mechanism of action is incompletely understood. Here, we found that fenofibrate dramatically modulate the gut microbiota composition of high-fat diet (HFD)-induced NAFLD mouse model, and the change of gut microbiota composition is dependent on TFEB-autophagy axis. Furthermore, we also found that fenofibrate improved hepatic steatosis, and increased the activation of TFEB, which severed as a regulator of autophagy, thus, the protective effects of fenofibrate against NAFLD are depended on TFEB-autophagy axis. Our study demonstrates the host gene may influence the gut microbiota and highlights the role of TFEB and autophagy in the protective effect of NAFLD. This work expands our understanding of the regulatory interactions between the host and gut microbiota and provides novel strategies for alleviating obesity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Chronic interstitial fibrosis is the primary barrier against the long-term survival of transplanted kidneys. Extending the lifespan of allografts is vital for ensuring the long-term health of patients undergoing kidney transplants. However, few targets and their clinical applications have been identified. Moreover, whether dyslipidemia facilitates fibrosis in renal allograft remains unclear., Methods: Blood samples were collected from patients who underwent kidney transplantation. Correlation analyses were conducted between the Banff score and body mass index, and serum levels of triacylglycerol, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. A rat model of renal transplantation was treated with the lipid-lowering drug, fenofibrate, and kidney fibrosis levels were determined by histochemical staining. Targeted metabolomic detection was conducted in blood samples from patients who underwent kidney transplantation and were divided into fibrotic and non-fibrotic groups. Rats undergoing renal transplantation were fed either an n-3 or n-6 polyunsaturated fatty acid (PUFA)-enriched diet. Immunohistochemical and Masson's trichrome staining were used to determine the degree of fibrosis., Results: Hyperlipidemia was associated with fibrosis development. Treatment with fenofibrate contributed to improve fibrosis in a rat model of renal transplantation. Moreover, n-3 PUFAs from fibrotic group showed significant downregulation compared to patients without fibrotic renal allografts, and n-3 PUFAs-enriched diet contributed to delayed fibrosis in a rat model of renal transplantation., Conclusions: This study suggests that hyperlipidemia facilitates fibrosis of renal allografts. Importantly, a new therapeutic approach was provided that may delay chronic interstitial fibrosis in transplanted kidneys by augmenting the n-3 PUFA content in the diet., (© 2023. The Author(s).)

Purpose: This study aimed to determine the effect and its mechanism of fenofibrate on retinal pigment epithelium (RPE) injury induced by excessive fat in vitro and in vivo., Methods: ARPE-19 cells were co-incubated with palmitic acid (PA) and fenofibric acid (the active form of fenofibrate after metabolism in vivo) and mice fed with high-fat diet (HFD) were supplemented with fenofibrate. The following methods were used: Western blot and immunofluorescent staining to determine expressions of reactive oxygen species (ROS)-associated factors and proinflammatory cytokines; electroretinogram (ERG) c-wave to evaluate RPE function; TUNEL staining to detect the apoptotic cell in RPE tissue. Additionally, ARPE19 cells were treated with PI3K/AKT inhibitor or agonist to investigate the mechanism of fenofibric acid inhibiting PA-induced RPE damage., Results: We found that the application of PA inhibited RPE cell viability in a dose-dependent manner, and increased the levels of NAPDH oxidase 4 (NOX4), 3-nitrotyrosin (3-NT), intracellular adhesion molecule-1(ICAM1), tumor necrosis factor alpha (TNFα) and vascular endothelial growth factor (VEGF) at 400μM. The application of fenofibric acid resulted in the inhibition of NOX4, 3-NT, TNFα, ICAM1 and VEGF expression in ARPE-19 cells treated with PA. Moreover, wortmannin, as a selective inhibitor of PI3K/AKT pathway, abolished the effects of fenofibrate on the oxidative stress and inflammation in ARPE-19 cells. In addition, 740Y-P, a selective agonist of PI3K/AKT pathway, enhanced the protective action of fenofibrate. Meanwhile, in vivo dosing of fenofibrate ameliorated the downregulated amplitudes of ERG c-wave in HFD-fed mice and suppressed the HFD-induced oxidative injury and inflammatory response in RPE tissues., Conclusion: Our results suggested that fenofibrate ameliorated RPE cell damage induced by excessive fat in vitro and in vivo, in part, through activation of the PI3K/AKT signaling pathway., Competing Interests: The authors report no conflicts of interest in this work., (© 2023 Wang et al.)

Background: Fenofibrate is a hypolipidemic peroxisome proliferator-activated receptor α (PPARα) agonist used clinically to reduce hypercholesterolemia and hypertriglyceridemia., Objective: We investigated the effects of fenofibrate on insulin resistance and tissue inflammation in a high-fat diet (HFD)-fed ovariectomized (OVX) C57BL/6J mice, a mouse model of obese postmenopausal women., Methods: Female OVX mice were randomly divided into 3 groups and received a low-fat diet, an HFD, or an HFD supplemented with 0.05% (w/w) fenofibrate for 9 weeks. Parameters of insulin resistance and tissue inflammation were measured using blood analysis, histological analysis, immunohistochemistry, and quantitative real-time polymerase chain reaction., Results: When fenofibrate was administered to HFD-fed OVX mice for 9 weeks, we observed reductions in body weight gain, adipose tissue mass, and the size of visceral adipocytes without the change of food intake. Fenofibrate improved mild hyperglycemia, severe hyperinsulinemia, and glucose tolerance in these mice. It also reduced pancreatic islet size and insulin-positive β-cell area to levels similar to those in OVX mice fed a low-fat diet. Concomitantly, administration of fenofibrate not only suppressed pancreatic lipid accumulation but also decreased CD68-positive macrophages in both the pancreas and visceral adipose tissue. Treatment with fenofibrate reduced tumor necrosis factor α (TNFα) mRNA levels in adipose tissue and lowered serum TNFα levels., Conclusion: These results suggest that fenofibrate treatment attenuates insulin resistance in part by reducing tissue inflammation and TNFα expression in HFD-fed OVX mice., (© 2023. The Author(s).)

Telomere length, a marker of ageing, is susceptible to developmental programming that may cause its accelerated attrition. Metabolic syndrome triggers telomere attrition. Fenofibrate, a peroxisome proliferator-activated receptor-alpha agonist, is protective against telomere attrition. We investigated the impact of fenofibrate administered during suckling on the lipid profile and leucocyte telomere lengths of rats fed a high-fructose diet post-weaning. Suckling Sprague-Dawley pups ( n  = 119) were allocated to four groups and gavaged with either 10 mL·kg -1 body mass 0.5% dimethyl sulfoxide, 100 mg·kg -1 body mass fenofibrate, fructose (20%, w / v ), or a combination of fenofibrate and fructose for 15 days. Upon weaning, each of the initial groups was split into two subgroups: one had plain water while the other had fructose solution (20%, w / v ) to drink for 6 weeks. Blood was collected for DNA extraction and relative leucocyte telomere length determination by real-time PCR. Plasma triglycerides and cholesterol were also quantified. The treatments had no effect ( p  > 0.05) on body mass, cholesterol concentration, and relative leucocyte telomere lengths in both sexes. Post-weaning fructose increased triglyceride concentrations ( p  < 0.05) in female rats. Fenofibrate administered during suckling did not affect ageing nor did it prevent high fructose-induced hypertriglyceridaemia in female rats., Competing Interests: The authors declare there are no competing interests.

One of the most significant chemotherapeutic side effects of cisplatin (Cis) that limits its use and efficacy is testicular toxicity. Thus, the objective of the present study was to investigate the possible ameliorative effect of Fenofibrate (Fen), Diosmetin (D), and their combination against cis-mediated testicular damage. Fifty-four adult male albino rats were randomly allocated into nine groups (6 rats each): Control group, Fen (100 mg/kg), D20 (20 mg/kg), D40 (40 mg/kg), Cis group (7 mg/kg), Cis +Fen group (7 mg/kg+100 mg/kg), Cis+D20 group (7 mg/kg+20 mg/kg), Cis+D40 group (7 mg/kg+40 mg/kg), Cis+Fen+D40 treated group (7 mg/kg+100 mg/kg+40 mg/kg). Relative testicular weight, epididymal sperm count and viability, serum testosterone level, testicular oxidative stress indices, mRNA expression of peroxisome proliferator-activated receptor alpha (PPAR-α), nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1), histopathological, and immunohistochemical alterations were assessed. Our results revealed that cis administration induced testicular oxidative and inflammatory damage as indicated by a substantial reduction in relative testicular weight, sperm parameters, serum testosterone levels, the antioxidant enzyme activity of catalase, and Johnson's histopathological score, PPAR-α/NRF-2/HO-1 and proliferating cell nuclear antigen (PCNA) immunoexpression with marked increment in malondialdehyde (MDA), Cosentino's score, nuclear factor kappa B (NF-κβ p65), interleukin (IL)- 1β and caspase 3 in testicular tissue. Interestingly, Fen and D diminished the harmful effects of cis on testes via upregulation of the antioxidant activities and downregulation of lipid peroxidation, apoptosis, and inflammation. Moreover, the combination therapy Fen/D40 also exhibited a more pronounced enhancement of previous markers than either treatment alone. In conclusion, because of their antioxidant, anti-inflammatory, and anti-apoptotic properties, cotreatment with Fen or D or their combination could be beneficial in reducing the harmful impacts of cis on testicular tissue, particularly in patients that receive cis chemotherapy., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Pemafibrate is a novel fibrate class drug that is a highly potent and selective agonist of peroxisome proliferator-activated receptor α (PPARα). We performed the first ever network meta-analysis containing the largest ever group of patients to test the efficacy of pemafibrate in improving lipid levels compared with fenofibrate and placebo in patients with dyslipidemia., Methods: Potentially relevant clinical trials were identified in Medline, PubMed, Embase, clinicaltrials.gov, and Cochrane Controlled Trials registry. Nine randomized controlled trials met the inclusion criteria out of 40 potentially available articles. The primary effect outcome was a change in the levels of triglycerides (TG), high-density lipoproteins (HDL), or low-density lipoproteins (LDL) before and after the treatment., Results: A total of 12,359 subjects were included. The mean patient age was 54.73 (years), the mean ratio for female patients was 18.75%, and the mean examination period was 14.22 weeks. The dose for pemafibrate included in our study was 0.1, 0.2, or 0.4 mg twice daily, whereas the dose for fenofibrate was 100 mg/day. Data showed a significant reduction in TG and a mild increase in HDL levels across the pemafibrate group at different doses and fenofibrate 100 mg group (with greatest effect observed with pemafibrate 0.1 mg twice daily). A mild increase in LDL was also observed in all groups, but the increase in LDL in the 0.1 mg twice daily dose group was statistically insignificant., Conclusion: Pemafibrate 0.1 mg twice daily dose led to highest reduction in TG levels and the highest increase in HDL levels compared with other doses of pemafibrate, fenofibrate, and placebo., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

IL-17A is a critical pro-inflammatory cytokine in autoimmune diseases such as psoriasis. Targeting of IL-17A is an effective strategy to treat patients with autoimmune diseases; however, relevant small molecule therapeutics have not yet been developed. Here, the small molecule drug fenofibrate was validated as an inhibitor of IL-17A through ELISA and surface plasmon resonance (SPR) assays. We further confirmed that fenofibrate blocked IL-17A signalings including the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways, in IL-17A-treated HaCaT cells, HEKa (human primary epidermal keratinocytes) and imiquimod (IMQ)-induced psoriasis mouse model. Fenofibrate attenuated systemic inflammation by suppressing Th17 populations and inflammatory cytokines, such as IL-1β, IL-6, IL-17A, and tumor necrosis factor (TNF). Surprisingly, fenofibrate upregulated LC3 and p62 in the psoriatic mouse group. The autophagy changes were caused by ULK1 pathway in hIL-17A-treated HaCaT and HEKa. In addition, the enhancement of autophagy by fenofibrate exerted anti-inflammatory effects, as demonstrated by the suppression of IL-6 and IL-8 in the IL-17A-treated keratinocytes. Thus, IL-17A-targeting fenofibrate can be a potential therapeutic for psoriasis and other autoimmune diseases via regulating autophagy., Competing Interests: Declaration of competing interest The authors state no conflict of the interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background/aim: Asthma is a chronic inflammatory disease of the airways with a high prevalence. Asthma has a complex pathophysiology and about 5-10% of patients are not fully responsive to the currently available treatments. The aim of this study is to investigate the involvement of NF-κB in the effects of fenofibrate on a mouse model of allergic asthma., Materials and Methods: A total of 49 BALB/c mice were randomly distributed into 7 groups (n = 7). Allergic asthma model was created by administering i.p. injections of ovalbumin on days 0, 14 and 21, followed by provocation with inhaled ovalbumin on days 28, 29 and 30. Fenofibrate was orally given in 3 different doses; 1, 10 and 30 mg/kg through days 21-30 of the experiment. On day 31, pulmonary function test using whole body plethysmography was performed. The mice were sacrificed 24 h later. Blood samples were obtained, and serum of each sample was separated for IgE determination. Bronchoalveolar lavage fluid (BALF) and lung tissues were collected to measure IL-5 and IL-13 levels. Nuclear extracts of lung tissues were employed to assess nuclear factor kappa B (NF-κB) p65 binding activity., Results: Enhanced Pause (Penh) values were significantly increased in ovalbumin-sensitized and challenged mice (p < 0.01). Administration of fenofibrate (10 and 30 mg/kg) resulted in improved pulmonary function as shown by significantly lower Penh values (p < 0.01). Interleukin (IL) - 5 and IL-13 levels in BALF and lung tissues and immunoglobulin E (IgE) levels in serum were significantly elevated in the allergic mice. IL-5 levels in the lung tissues of mice treated with 1 mg/kg fenofibrate (FEN1) group were significantly reduced (p < 0.01). BALF and lung tissue IL-5 and IL-13 levels in mice treated with 10 and 30 mg/kg fenofibrate, FEN10 and FEN30, respectively, were significantly diminished when compared to the ovalbumin-treated (OVA) group, whereas treatment with 1 mg/kg fenofibrate resulted in insignificant changes. IgE levels in the serum of FEN30 group mice have shown a prominent reduction (p < 0.01). NF-κB p65 binding activity was higher in mice sensitized and challenged with ovalbumin (p < 0.01). NF-κB p65 binding activity was significantly reduced in allergic mice treated with 30 mg/kg (p < 0.01) fenofibrate., Conclusions: In this study, we showed that administration of 10 and 30 mg/kg fenofibrate effectively attenuated airway hyperresponsiveness and inflammation in a mouse model of allergic asthma, possibly through inhibition of NF-κB binding activity., Competing Interests: Declaration of Competing Interest The authors declare that there is no conflict of interests., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Fenofibrate (FEN) is an antilipidemic drug that increases the activity of the lipoprotein lipase enzyme, thus enhancing lipolysis; however, it may cause myopathy and rhabdomyolysis in humans. Coenzyme Q10 (CoQ10) is an endogenously synthesized compound that is found in most living cells and plays an important role in cellular metabolism. It acts as the electron carrier in the mitochondrial respiratory chain. This study aimed to elucidate FEN-induced skeletal muscle changes in rats and to evaluate CoQ10 efficacy in preventing or alleviating these changes. Forty adult male rats were divided equally into four groups: the negative control group that received saline, the positive control group that received CoQ10, the FEN-treated group that received FEN, and the FEN + CoQ10 group that received both FEN followed by CoQ10 daily for 4 weeks. Animals were sacrificed and blood samples were collected to assess creatine kinase (CK). Soleus muscle samples were taken and processed for light and electron microscopic studies. This study showed that FEN increased CK levels and induced inflammatory cellular infiltration and disorganization of muscular architecture with lost striations. FEN increased the percentage of degenerated collagen fibers and immune expression of caspase-3. Ultrastructurally, FEN caused degeneration of myofibrils with distorted cell organelles. Treatment with CoQ10 could markedly ameliorate these FEN-induced structural changes and mostly regain the normal architecture of muscle fibers due to its antifibrotic and antiapoptotic effects. In conclusion, treatment with CoQ10 improved muscular structure by suppressing oxidative stress, attenuating inflammation, and inhibiting apoptosis., (© 2023. The Author(s).)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emergence in 2019 led to global health crises and the persistent risk of viral mutations. To combat SARS-CoV-2 variants, researchers have explored new approaches to identifying potential targets for coronaviruses. This study aimed to identify SARS-CoV-2 inhibitors using drug repurposing. In silico studies and network pharmacology were conducted to validate targets and coronavirus-associated diseases to select potential candidates, and in vitro assays were performed to evaluate the antiviral effects of the candidate drugs to elucidate the mechanisms of the viruses at the molecular level and determine the effective antiviral drugs for them. Plaque and cytopathic effect reduction were evaluated, and real-time quantitative reverse transcription was used to evaluate the antiviral activity of the candidate drugs against SARS-CoV-2 variants in vitro. Finally, a comparison was made between the molecular docking binding affinities of fenofibrate and remdesivir (positive control) to conventional and identified targets validated from protein-protein interaction (PPI). Seven candidate drugs were obtained based on the biological targets of the coronavirus, and potential targets were identified by constructing complex disease targets and PPI networks. Among the candidates, fenofibrate exhibited the strongest inhibition effect 1 h after Vero E6 cell infection with SARS-CoV-2 variants. This study identified potential targets for coronavirus disease (COVID-19) and SARS-CoV-2 and suggested fenofibrate as a potential therapy for COVID-19., (© 2023. The Author(s), under exclusive licence to Microbiological Society of Korea.)

Diabetic corneal neuropathy (DCN) is a common complication of diabetes. However, there are very limited therapeutic options. We investigated the effects of a peroxisome proliferator-activated receptor-α (PPAR-α) agonist, fenofibrate, on 30 patients (60 eyes) with type 2 diabetes. On in vivo confocal microscopy evaluation, there was significant stimulation of corneal nerve regeneration and a reduction in nerve edema after 30 days of oral fenofibrate treatment, as evidenced by significant improvement in corneal nerve fiber density (CNFD) and corneal nerve fiber width, respectively. Corneal epithelial cell morphology also significantly improved in cell circularity. Upon clinical examination, fenofibrate significantly improved patients' neuropathic ocular surface status by increasing tear breakup time along with a reduction of corneal and conjunctival punctate keratopathy. Tear substance P (SP) concentrations significantly increased after treatment, suggesting an amelioration of ocular surface neuroinflammation. The changes in tear SP concentrations was also significantly associated with improvement in CNFD. Quantitative proteomic analysis demonstrated that fenofibrate significantly upregulated and modulated the neurotrophin signaling pathway and linolenic acid, cholesterol, and fat metabolism. Complement cascades, neutrophil reactions, and platelet activation were also significantly suppressed. Our results showed that fenofibrate could potentially be a novel treatment for patients with DCN., (© 2023 by the American Diabetes Association.)

Monocyte activation plays an important role in diabetic complications such as diabetic retinopathy (DR). However, the regulation of monocyte activation in diabetes remains elusive. Fenofibrate, an agonist of peroxisome proliferator-activated receptor-α (PPARα), has shown robust therapeutic effects on DR in patients with type 2 diabetes. Here we found that PPARα levels were significantly downregulated in monocytes from patients with diabetes and animal models, correlating with monocyte activation. Fenofibrate attenuated monocyte activation in diabetes, while PPARα knockout alone induced monocyte activation. Furthermore, monocyte-specific PPARα overexpression ameliorated, while monocyte-specific PPARα knockout aggravated monocyte activation in diabetes. PPARα knockout impaired mitochondrial function while also increasing glycolysis in monocytes. PPARα knockout increased cytosolic mitochondrial DNA release and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in monocytes under diabetic conditions. STING knockout or STING inhibitor attenuated monocyte activation induced by diabetes or by PPARα knockout. These observations suggest that PPARα negatively regulates monocyte activation through metabolic reprogramming and interaction with the cGAS-STING pathway., (© 2023 by the American Diabetes Association.)

Cytotoxic T lymphocytes (CTLs) are central effector cells in antitumor immunotherapy. However, the complexity of immunosuppressive factors in the immune system contributes to the low response rates of current CTL-based immunotherapies. Here, we propose a novel holistic strategy including a priming response, promoting activity, and relieving suppression of CTLs, aiming to strengthen the effect of personalized postoperative autologous nanovaccines. The nanovaccine (C/G-HL-Man) fused the autologous tumor cell membrane with dual adjuvants (CpG and cGAMP), and could effectively accumulate in lymph nodes and promote antigen cross presentation by dendritic cells to prime a sufficient specific-CTL response. The PPAR-α agonist fenofibrate was used to regulate T-cell metabolic reprogramming to promote antigen-specific CTLs activity in the harsh metabolic tumor microenvironment. Finally, the PD-1 antibody was used to relieve the suppression of specific-CTLs in the immunosuppressive tumor microenvironment. In vivo, the C/G-HL-Man exhibited strong antitumor effect in the B16F10 murine tumor prevention model and the B16F10 postoperative recurrence model. In particular, combination therapy with nanovaccines, fenofibrate, and PD-1 antibody effectively inhibited the progression of recurrent melanoma and prolonged the survival time. Our work highlights the critical role of the T-cell metabolic reprogramming and PD-1 blocking in autologous nanovaccines, offering a novel strategy for strengthening the function of CTLs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Doxorubicin (DOX) is one of the basic anticancer drugs, nonetheless its use is restricted due to noxious side effects. Kidney failure is one of the main side effects that restrict its medical use. The current study assessed the nephroprotective effects of fenofibrate and pioglitazone against the renal injury induced by doxorubicin in rats and illustrated the probable mechanisms underlying these protective effects. For this purpose, Male Sprague-Dawley rats weighing (200-230 g) were allocated into seven groups treated for 15 days as following: control (50% corn oil + 50% DMSO p.o), fenofibrate (100 mg/kg p.o) and pioglitazone (10 mg/kg p.o) as well as four groups of DOX (15 mg/kg i.p on 11th day). DOX groups included DOX alone and DOX with protective drugs fenofibrate, pioglitazone or both of them. As a result of doxorubicin nephrotoxicity; serum creatinine and blood urea nitrogen were remarkably elevated. Moreover, renal glutathione was significantly reduced while tissue lipid peroxidation malondialdehyde, tumor necrosis factor-α, nuclear factor-kappa B p65 (NF-κB p65), interleukin-1β, p38 mitogen activated protein kinase (p38-MAPK) and caspase-3 (Casp-3) were significantly augmented. Treatment with fenofibrate and pioglitazone either alone or in combination markedly attenuated DOX-induced injury by suppression of oxidative stress, inflammation and apoptosis. The above-mentioned biochemical markers were affirmed by histological assessment. In conclusion, fenofibrate, pioglitazone, and their combination possess potential prophylactic effects against doxorubicin-induced renal injury through modulation of p38-MAPK/NF-κB p65 pathway with superiority to the combination., (© 2023 Wiley Periodicals LLC.)

Background: Diabetic kidney disease (DKD) is a major diabetic microvascular complication. Fatty acid-induced lipotoxicity and apoptosis were associated with the exacerbation of DKD. However, the association of lipotoxicity with renal tubular apoptosis and the effects of fenofibrate on DKD are not fully understood., Methods: Eight-week-old db/db mice were given fenofibrate or saline by gavage for 8 weeks. Human kidney proximal tubular epithelial (HK2) cells stimulated with palmitic acid (PA) and high glucose (HG) were used as a model of lipid metabolism disorders. Apoptosis was assessed with or without fenofibrate. The AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and AMPK inhibitor Compound C were used to determine the involvement of AMPK and Medium-chain acyl-CoA dehydrogenase (MCAD) in the regulation of lipid accumulation by fenofibrate. MCAD silencing was achieved by small interfering RNA (siRNA) transfection., Results: Fenofibrate reduced triglyceride (TG) content and lipid accumulation in DKD. Importantly, renal function and tubular cell apoptosis were significantly improved by fenofibrate. Fenofibrate reduced apoptosis, accompanied by increased activation of the AMPK/FOXA2/MCAD pathway. MCAD silencing resulted in apoptosis and lipid accumulation despite fenofibrate treatment., Conclusion: Fenofibrate improves lipid accumulation and apoptosis through the AMPK/FOXA2/MCAD pathway. MCAD may be a potential therapeutic target of DKD, and the use of fenofibrate as a treatment for DKD warrants further study., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Tang et al.)

Aims: Peroxisome proliferator-activated receptor-alpha (PPARα) levels are markedly lower in the kidneys of chronic kidney disease (CKD) patients. Fibrates (PPARα agonists) are therapeutic agents against hypertriglyceridemia and potentially against CKD. However, conventional fibrates are eliminated by renal excretion, limiting their use in patients with impaired renal function. Here, we aimed to evaluate the renal risks associated with conventional fibrates via clinical database analysis and investigate the renoprotective effects of pemafibrate, a novel selective PPARα modulator mainly excreted into the bile., Main Methods: The risks associated with conventional fibrates (fenofibrate, bezafibrate) to the kidneys were evaluated using the Food and Drug Administration Adverse Event Reporting System. Pemafibrate (1 or 0.3 mg/kg/day) was administered daily using an oral sonde. Its renoprotective effects were examined in unilateral ureteral obstruction (UUO)-induced renal fibrosis model mice (UUO mice) and adenine-induced CKD model mice (CKD mice)., Key Findings: The ratios of glomerular filtration rate decreased and blood creatinine increased were markedly higher after conventional fibrate use. Pemafibrate administration suppressed increased gene expressions of collagen-I, fibronectin, and interleukin 1 beta (IL-1β) in the kidneys of UUO mice. In CKD mice, it suppressed increased plasma creatinine and blood urea nitrogen levels and decreased red blood cell count, hemoglobin, and hematocrit levels, along with renal fibrosis. Moreover, it inhibited the upregulation of monocyte chemoattractant protein-1, IL-1β, tumor necrosis factor-alpha, and IL-6 in the kidneys of CKD mice., Significance: These results demonstrated the renoprotective effects of pemafibrate in CKD mice, confirming its potential as a therapeutic agent for renal disorders., Competing Interests: Declaration of competing interest Pemafibrate was provided by Kowa Company, Ltd. (Tokyo, Japan). There are no further patents, products in development, or marketed products to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Purpose: Robust, affordable plasma proteomic biomarker workflows are needed for large-scale clinical studies. We evaluated aspects of sample preparation to allow liquid chromatography-mass spectrometry (LC-MS) analysis of more than 1500 samples from the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial of adults with type 2 diabetes., Methods: Using LC-MS with data-independent acquisition we evaluated four variables: plasma protein depletion, EDTA or citrated anti-coagulant blood collection tubes, plasma lipid depletion strategies and plasma freeze-thaw cycles. Optimised methods were applied in a pilot study of FIELD participants., Results: LC-MS of undepleted plasma conducted over a 45 min gradient yielded 172 proteins after excluding immunoglobulin isoforms. Cibachrome-blue-based depletion yielded additional proteins but with cost and time expenses, while immunodepleting albumin and IgG provided few additional identifications. Only minor variations were associated with blood collection tube type, delipidation methods and freeze-thaw cycles. From 65 batches involving over 1500 injections, the median intra-batch quantitative differences in the top 100 proteins of the plasma external standard were less than 2%. Fenofibrate altered seven plasma proteins., Conclusions and Clinical Relevance: A robust plasma handling and LC-MS proteomics workflow for abundant plasma proteins has been developed for large-scale biomarker studies that balance proteomic depth with time and resource costs., (© 2023 The Authors. Proteomics - Clinical Applications published by Wiley-VCH GmbH.)

Inflammation contributes to the pathogenesis of several diseases. Fenofibrate, known as a peroxisome proliferator-activated receptor - α (PPAR-α) agonist, is a classic drug for treating hyperlipidemia. In addition to its lipid-lowering effect, fenofibrate has also been reported to exert anti-inflammatory effects with complicated underlying mechanisms of action. In general, the anti-inflammatory effect of fenofibrate is secondary to its lipid-lowering effect, especially for the inflammation caused by hyperlipidemia in the circulatory system. Some anti-inflammatory actions may also come from its regulatory effects on intracellular lipid metabolism by activating PPAR-α. In addition, some roles in anti-inflammation might be mediated by its direct regulation of inflammatory signaling pathways. In order to understand anti-inflammatory activities and the underlying mechanisms of fenofibrate action in disease better, we herein reviewed and discussed the anti-inflammatory roles and its subserving mechanisms in various diseases of different organ systems. Thus, this review offers insights into the optimal use of fenofibrate in the clinical setting.

Background: Sirtuin 1 (Sirt1) and sirtuin 3 (Sirt3) participate in the regulation of lipid metabolism. Our aim was to investigate the effects of the hypolipemic drug fenofibrate (FN) on hepatic Sirt1 and Sirt3 expression, in relation to the expression of lipid metabolism-related genes and in the context of aging., Methods and Results: Young and old male Wistar rats were fed standard chow or supplemented with 0.1% or 0.5% FN for 30 days (n=7-10 in each group). In young rats, 0.1% FN did not affect Sirt1 expression, however, 0.5% FN decreased Sirt1 and both doses reduced Sirt3 protein levels. In old rats, 0.5% FN decreased hepatic Sirt1 mRNA and both doses reduced Sirt1 protein levels, but not Sirt3 expression. Although hepatic Pparα protein levels did not change, FN treatment of young rats induced Cpt1b expression, whereas Lcad, Acox1, Pmp70, and Hmgcs2 expression increased only after 0.1% FN, and Fas2 expression decreased after 0.5% FN. In the liver of old rats, both doses increased Cpt1b and Lcad expression. Only 0.1% FN increased Pmp70 and Hmgcs2 expression, and only 0.5% FN increased Acox1 and Fas2 mRNA levels., Conclusions: Treatment with fenofibrate at low or high doses may downregulate the expression of Sirt1 and Sirt3 proteins in the rat liver. The dosage of FN affects molecular changes, and aging alters the response to 0.5% FN.

The objective of study was to investigate the effects of different doses of simvastatin and fenofibrate on malondialdehyde (MDA) and reduced glutathione (GSH) in the plasma, liver, and brain tissue of male normolipidaemic and hyperlipidaemic rats. Normolipidaemic (Wistar) rats were receiving 10 or 50 mg/kg a day of simvastatin or 30 or 50 mg/kg a day of fenofibrate. Hyperlipidaemic (Zucker) rats were receiving 50 mg/kg/day of simvastatin or 30 mg/kg/day of fenofibrate. Control normolipidaemic and hyperlipidaemic rats were receiving saline. Simvastatin, fenofibrate, and saline were administered by gavage for three weeks. In normolipidaemic rats simvastatin and fenofibrate showed similar and dose-independent effects on plasma and brain MDA and GSH concentrations. Generally, plasma and brain MDA decreased, while brain GSH concentration increased. In hyperlipidaemic rats simvastatin did not affect plasma and brain MDA and GSH concentrations but significantly decreased liver GSH. Fenofibrate decreased plasma and liver MDA but increased brain MDA. In both rat strains fenofibrate significantly decreased liver GSH concentrations, most likely because fenofibrate metabolites bind to GSH. Our findings suggest that simvastatin acts as an antioxidant only in normolipidaemic rats, whereas fenofibrate acts as an antioxidant in both rat strains., (© 2023 Antonija Vukšić et al., published by Sciendo.)

The aim of this study was to examine the effects of the hypolipemic drug fenofibrate (FF) and aging on the expression of factors/enzymes involved in brown adipose tissue (BAT) function and browning of white adipose tissue epididymal (eWAT) and subcutaneous (sWAT) depots. Young-adult and old male Wistar rats were fed standard chow (control) or supplemented with 0.1% or 0.5% FF for 30 days. Tissue samples were analysed for gene expression and protein content, and stained with Oil Red O or hematoxylin and eosin. In BAT of young rats, 0.5% FF increased only Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 1 (CITED1) protein content and Fgf21 and Gpr109A mRNA expression. The expression of oxidative metabolism related genes (Pgc1α, Cpt1b, Mcad) decreased after 0.5% FF. In BAT of old rats, FF did not affect UCP1 and CITED1 content and had little effect on gene expression. Oil Red O staining of BAT revealed no changes in lipid droplet area upon treatment in either age group. In eWAT of young rats, 0.1FF elevated UCP1 protein content and Ucp1, Pgc-1α, and Mcad expression, whereas 0.5% FF increased PPARα content and Pgc-1α, Cpt1b, Mcad, and Gpr109A levels. In eWAT of old rats, only 0.1FF increased Pgc1α and Mcad expression. In both age groups median cell area of eWAT adipocytes was reduced after 0.5% FF. In sWAT Ucp1 gene expression was very low and UCP1 protein was undetectable. FF upregulated Ucp1, Cited1, Eva1, and Cpt1b expression in sWAT of young rats, with diminished effects in old rats. In both age groups 0.5% FF increased Fgf21 expression in sWAT. Median cell area of sWAT adipocytes decreased only in young rats treated with 0.5% FF. Our results reveal that fenofibrate differentially affects gene expression in BAT, with diminished effects in old compared to young rats. In WAT of young rats FF modestly stimulates the expression of factors/enzymes involved in lipid oxidative metabolism and browning. Aging reduces both these effects. Gpr109A may present a novel gene target upregulated by FF in BAT and eWAT.

Acerola (Malpighia emarginata) by-product (ABP) has various bioactive compounds with hypoglycaemic, antioxidant and anti-inflammatory activity. The ABP effects on the biochemical changes in the enterohepatic axis caused by a high-fat diet (HFD) remains unclear. This study assessed whether the ABP or fenofibrate administration for 28 days interferes in lipid, glucose, or inflammatory changes in the enterohepatic axis of rats fed HFD. ABP induced in the rats fed HFD a reduction in body weight, serum lipids, blood glucose, and liver fat accumulation; increased insulin tolerance, and faecal bile acid excretion; regulated organic acid synthesis, faecal and colonic microbial growth; reduced M1 macrophage and increased M2 macrophage infiltration in the colon and liver, respectively. The fenofibrate did not improve the lipid or glucose alterations in enterohepatic axis of rats fed HFD. ABP has functional/nutraceutical potential in treating HFD-induced metabolic disorders with beneficial effects on lipid and glucose metabolism, and reduction of inflammation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Treatment with acetyl-CoA carboxylase inhibitors (ACCi) in nonalcoholic steatohepatitis (NASH) may increase plasma triglycerides (TGs), with variable changes in apoB concentrations. ACC is rate limiting in de novo lipogenesis and regulates fatty acid oxidation, making it an attractive therapeutic target in NASH. Our objectives were to determine the effects of the ACCi, firsocostat, on production rates of plasma LDL-apoB in NASH and the effects of combined therapy with fenofibrate. Metabolic labeling with heavy water and tandem mass spectrometric analysis of LDL-apoB enrichments was performed in 16 NASH patients treated with firsocostat for 12 weeks and in 29 NASH subjects treated with firsocostat and fenofibrate for 12 weeks. In NASH on firsocostat, plasma TG increased significantly by 17% from baseline to week 12 (P = 0.0056). Significant increases were also observed in LDL-apoB fractional replacement rate (baseline to week 12: 31 ± 20.2 to 46 ± 22.6%/day, P = 0.03) and absolute synthesis rate (ASR) (30.4-45.2 mg/dl/day, P = 0.016) but not plasma apoB concentrations. The effect of firsocostat on LDL-apoB ASR was restricted to patients with cirrhosis (21.0 ± 9.6 at baseline and 44.2 ± 17 mg/dl/day at week 12, P = 0.002, N = 8); noncirrhotic patients did not change (39.8 ± 20.8 and 46.3 ± 14.8 mg/dl/day, respectively, P = 0.51, N = 8). Combination treatment with fenofibrate and firsocostat prevented increases in plasma TG, LDL-apoB fractional replacement rate, and ASR. In summary, in NASH with cirrhosis, ACCi treatment increases LDL-apoB100 production rate and this effect can be prevented by concurrent fenofibrate therapy., Competing Interests: Conflict of interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The nuclear receptor peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that controls the transcription of genes responsible for fatty acid metabolism. We have recently reported a possible drug-drug interaction mechanism via the interaction of PPARα with the xenobiotic nuclear receptor constitutive androstane receptor (CAR). Drug-activated CAR competes with the transcriptional coactivator against PPARα and prevents PPARα-mediated lipid metabolism. In this study, to elucidate the crosstalk between CAR and PPARα, we focused on the influence of PPARα activation on CAR's gene expression and activation. Male C57BL/6N mice (8-12 weeks old, n = 4) were treated with PPARα and CAR activators (fenofibrate and phenobarbital, respectively), and hepatic mRNA levels were determined using quantitative reverse transcription PCR. Reporter assays using the mouse Car promoter were performed in HepG2 cells to determine the PPARα-dependent induction of CAR. CAR KO mice were treated with fenofibrate, and the hepatic mRNA levels of PPARα target genes were determined. Treatment of mice with a PPARα activator increased Car mRNA levels as well as genes related to fatty acid metabolism. In reporter assays, PPARα induced the promoter activity of the Car gene. Mutation of the putative PPARα-binding motif prevented PPARα-dependent induction of reporter activity. In electrophoresis mobility shift assay, PPARα bound to the DR1 motif of the Car promoter. Since CAR has been reported to attenuate PPARα-dependent transcription, CAR was considered a negative feedback protein for PPARα activation. Treatment with fenofibrate induced the mRNA levels of PPARα target genes in Car -null mice more than those in wild-type mice, suggesting that CAR functions as a negative feedback factor for PPARα.