Selective PPARα Agonist Research Articles

New PPARα Agonist A190-Loaded Microemulsion for Chemotherapy-Induced Peripheral Neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of anticancer agents with limited effective preventive or therapeutic interventions. Although fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, has demonstrated neuroprotective and analgesic properties, its clinical utility is hindered by low receptor affinity, poor subtype selectivity, and suboptimal bioavailability. A190, a highly selective and potent nonfibrate PPARα agonist, offers a promising alternative but is limited by poor aqueous solubility, resulting in reduced oral bioavailability and therapeutic efficacy. To address these limitations, an optimized oil-in-water (o/w) microemulsion formulation was developed using Box-Behnken design to enhance the solubility and intestinal permeability of A190. The A190 microemulsion exhibited physical stability with a droplet size of approximately 100 nm and a drug loading efficiency of greater than 95%. The effective and apparent permeability of A190 from the microemulsion was significantly higher compared to that of free A190 dispersion, respectively. Additionally, no significant impact on the cell viability was observed, indicating less toxicity and a good biocompatibility of the formulation components. The oral bioavailability of A190 microemulsion was approximately 5-fold higher compared to A190 dispersion, demonstrating the microemulsion's potential to greatly enhance the oral bioavailability of hydrophobic drugs. Furthermore, our findings reveal that orally administered A190 microemulsion effectively reduced CIPN-induced mechanical hypersensitivity, likely mediated through PPARα activation. A190 microemulsion was found to be equally effective at reducing the chronic inflammatory complete Freund's adjuvant-induced pain. These results underscore A190s potential as a nonopioid therapeutic candidate, utilizing a novel microemulsion formulation for the management of chemotherapy-induced neuropathic pain and chronic inflammatory pain.

Oleuropein Promotes Neural Plasticity and Neuroprotection via PPARα-Dependent and Independent Pathways.

Oleuropein (OLE), a main constituent of olives, displays a pleiotropic beneficial dynamic in health and disease; the effects are based mainly on its antioxidant and hypolipidemic properties, and its capacity to protect the myocardium during ischemia. Furthermore, OLE activates the peroxisome proliferator-activated receptor (PPARα) in neurons and astrocytes, providing neuroprotection against noxious biological reactions that are induced following cerebral ischemia. The current study investigated the effect of OLE in the regulation of various neural plasticity indices, emphasizing the role of PPARα. For this purpose, 129/Sv wild-type (WT) and Pparα-null mice were treated with OLE for three weeks. The findings revealed that chronic treatment with OLE up-regulated the brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the prefrontal cortex (PFC) of mice via activation of the ERK1/2, AKT and PKA/CREB signaling pathways. No similar effects were observed in the hippocampus. The OLE-induced effects on BDNF and TrkB appear to be mediated by PPARα, because no similar alterations were observed in the PFC of Pparα-null mice. Notably, OLE did not affect the neurotrophic factors NT3 and NT4/5 in both brain tissues. However, fenofibrate, a selective PPARα agonist, up-regulated BDNF and NT3 in the PFC of mice, whereas the drug induced NT4/5 in both brain sites tested. Interestingly, OLE provided neuroprotection in differentiated human SH-SY5Y cells against β-amyloid and H2O2 toxicity independently from PPARα activation. In conclusion, OLE and similar drugs, acting either as PPARα agonists or via PPARα independent mechanisms, could improve synaptic function/plasticity mainly in the PFC and to a lesser extent in the hippocampus, thus beneficially affecting cognitive functions.

Efficacy and safety of pemafibrate versus bezafibrate in coronary artery disease patients receiving statin treatment: a randomized, open-label, cross-over study

Abstract Background Fibrates activate peroxisome proliferator-activated receptor (PPAR)-α which is associated with lipid metabolism. Bezafibrate is a non-selective PPAR-α agonist, whereas pemafibrate has been developed as a higher selective PPAR-α agonist. Objective The efficacy and safety of pemafibrate for 24-week in patients with dyslipidemia was examined in comparison with bezafibrate. Methods Sixty patients with hypertriglyceridemia (fasting triglyceride (TG) level of ≥150 mg/dL) were treated with pemafibrate of 0.2 mg/day or bezafibrate of 400 mg/day for 24-week in a randomized cross-over study. Percent change from baseline in TG levels was the primary endpoint, and that in HDL-C and apolipoprotein A-I (Apo A-I) levels was the secondary endpoints. Results A significantly greater reduction in TG percent change was observed in pemafibrate than in bezafibrate (−46.1% vs. −34.7%, p<0.001). There was no significant difference in HDL-C percent change between pemafibrate and bezafibrate (18.4% vs. 14.0%, p=0.067), whereas Apo A-I percent change was significantly greater in pemafibrate than in bezafibrate (9.2% vs. 5.7%, p=0.018). Pemafibrate and bezafibrate significantly decreased alanine aminotransferase (ALT) and gamma-glutamyltransferase (γ-GT) levels, and pemafibrate showed a greater reduction than bezafibrate (ALT: −21.9% vs. −10.6%, p=0.048; γ-GT: −43.5% vs. −33.1%, p=0.025). Creatinine levels significantly increased in both treatments (both p<0.001), however, creatinine percent change was significantly smaller in pemafibrate than in bezafibrate (5.72% vs. 15.5%, p<0.001). There was no difference in frequency of adverse event (AE) or serious AE between two treatments, but frequency of creatinine elevation (≥0.5 mg/d and/or 25%) was significantly higher in bezafibrate than in pemafibrate (16/60 vs. 3/60, p=0.004). Conclusion As compared with bezafibrate, pemafibrate is more effective to reduce TG levels and to elevate Apo A-I levels, and it is safer in terms of liver and renal function. Funding Acknowledgement Type of funding sources: None.

Pemafibrate attenuates pulmonary fibrosis by inhibiting myofibroblast differentiation

Background and ObjectiveIdiopathic pulmonary fibrosis is a chronic progressive disease associated with substantial morbidity and mortality despite advances in medical therapy. Increasing evidence suggests that peroxisome proliferator-activated receptors (PPARs) play important roles in the fibrosis-related diseases and their agonists may become effective therapeutic targets. Pemafibrate is a selective PPARα agonist, but the efficacy against pulmonary fibrosis and mechanisms involved have not been systematically evaluated. Thus, the aims of this study were to explore the role of PPARα in the pulmonary fibrosis and to assess the effect of pemafibrate in vivo and in vitro. MethodsThe effects of pemafibrate were evaluated in bleomycin-challenged murine pulmonary fibrosis model and transforming growth factor-beta 1 (TGF-β1) stimulated lung fibroblasts. ResultsBleomycin instillation induced body weight loss, declined lung function, pulmonary fibrosis, and extensive collagen deposition in the mice, accompanied with decreased pulmonary expression of PPARα, all of which were partially improved by pemafibrate at a dose of 2 mg/kg. Besides, pemafibrate effectively inhibits TGF-β1-induced myofibroblast differentiation and extracellular matrix (ECM) production in vivo and in vitro. Furthermore, we showed that pemafibrate not only inhibited pulmonary expression of NLRP3 and cleaved caspase-1 in bleomycin-inhaled mice, but also repressed activation of NLRP3/caspase-1 axis in TGF-β1 stimulated lung fibroblasts. ConclusionOur data suggest that pemafibrate exerts a marked protection against from the development of pulmonary fibrosis, which could constitute a novel candidate for the treatment for pulmonary fibrosis.

Highly Selective PPARα (Peroxisome Proliferator-Activated Receptor α) Agonist Pemafibrate Inhibits Stent Inflammation and Restenosis Assessed by Multimodality Molecular-Microstructural Imaging.

BACKGROUNDNew pharmacological approaches are needed to prevent stent restenosis. This study tested the hypothesis that pemafibrate, a novel clinical selective PPARα (peroxisome proliferator‐activated receptor α) agonist, suppresses coronary stent‐induced arterial inflammation and neointimal hyperplasia.METHODS AND RESULTSYorkshire pigs randomly received either oral pemafibrate (30 mg/day; n=6) or control vehicle (n=7) for 7 days, followed by coronary arterial implantation of 3.5 × 12 mm bare metal stents (2–4 per animal; 44 stents total). On day 7, intracoronary molecular‐structural near‐infrared fluorescence and optical coherence tomography imaging was performed to assess the arterial inflammatory response, demonstrating that pemafibrate reduced stent‐induced inflammatory protease activity (near‐infrared fluorescence target‐to‐background ratio: pemafibrate, median [25th‐75th percentile]: 2.8 [2.5–3.3] versus control, 4.1 [3.3–4.3], P=0.02). At day 28, animals underwent repeat near‐infrared fluorescence–optical coherence tomography imaging and were euthanized, and coronary stent tissue molecular and histological analyses. Day 28 optical coherence tomography imaging showed that pemafibrate significantly reduced stent neointima volume (pemafibrate, 43.1 [33.7–54.1] mm3 versus control, 54.2 [41.2–81.1] mm3; P=0.03). In addition, pemafibrate suppressed day 28 stent‐induced cellular inflammation and neointima expression of the inflammatory mediators TNF‐α (tumor necrosis factor‐α) and MMP‐9 (matrix metalloproteinase 9) and enhanced the smooth muscle differentiation markers calponin and smoothelin. In vitro assays indicated that the STAT3 (signal transducer and activator of transcription 3)–myocardin axes mediated the inhibitory effects of pemafibrate on smooth muscle cell proliferation.CONCLUSIONSPemafibrate reduces preclinical coronary stent inflammation and neointimal hyperplasia following bare metal stent deployment. These results motivate further trials evaluating pemafibrate as a new strategy to prevent clinical stent restenosis.

Integrative study of diet-induced mouse models of NAFLD identifies PPARα as a sexually dimorphic drug target

ObjectiveWe evaluated the influence of sex on the pathophysiology of non-alcoholic fatty liver disease (NAFLD). We investigated diet-induced phenotypic responses to define sex-specific regulation between healthy liver and NAFLD to...

The Effects of New Selective PPARα Agonist CP775146 on Systematic Lipid Metabolism in Obese Mice and Its Potential Mechanism.

Purpose Peroxisome proliferator-activated receptor α (PPARα) plays a crucial role in the control of lipid homeostasis. Here, we investigated the effects of CP775146, a new selective PPARα agonist, on lipid metabolism in diet-induced obese mice and its possible mechanism. Methods C57BL/6 mice were fed a high-fat diet (HFD) for 12 weeks to induce obesity and then received CP775146 via intraperitoneal injection for 3 days. The content/morphology of the liver, serum lipid, and liver function was measured. The expression of genes related to lipolysis and synthesis in liver was detected by quantitative real-time PCR (qRT-PCR). Results The safe dose of CP775146 was <0.3 mg/kg. CP775146 reduced the serum levels of liver enzymes, such as alanine aminotransferase (ALT) and glutamic-oxaloacetic transaminase (AST) and lipid metabolism-related biomarkers, including triglycerides (TGs) and low-density lipoprotein cholesterol (LDL-c), non-high-density lipoprotein cholesterol (non-HDL-c), and hepatic TG content, at a dosage of 0.1 mg/kg. HFD-induced pathological liver changes improved after CP775146 treatment. The expression of genes involved in liver fatty acid oxidation (acyl-coenzyme A dehydrogenase, long chain (Acadl), acyl-CoA oxidase 1 (Acox-1), carnitine palmitoyltransferase-1 (CPT-1), and enoyl-CoA, hydratase/3-hydroxyacyl CoA dehydrogenase (Ehhadh)) was upregulated in CP775146-treated mice. Furthermore, CP775146 induced the expression of thermogenesis genes (cell death-inducing DFFA-like effector a (Cidea), uncoupling protein 1 (Ucp1)) and lipolysis genes (hormone-sensitive lipase (Hsl), adipose tissue triglyceride lipase (Atgl)) in epididymal white adipose tissue (eWAT), activating browning and thermogenesis. Conclusion CP775146 efficiently alleviates obesity-induced liver damage, prevents lipid accumulation by activating the liver fatty acid β-oxidation pathway, and regulates the expression of genes that control brown fat-like pathway in eWAT.

Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages☆

Peroxisome proliferator-activated receptors (PPARs) are essential regulators of whole-body metabolism, but also modulate inflammation in immune cells, notably macrophages. We compared the effects of selective PPAR agonists to those of the pan-PPAR agonist lanifibranor in non-alcoholic fatty liver disease (NAFLD), and studied isoform-specific effects on hepatic macrophage biology. Lanifibranor or selective PPARα (fenofibrate), PPARγ (pioglitazone) and PPARδ (GW501516) agonists were therapeutically administered in choline-deficient, amino acid-defined high-fat diet (CDAA-HFD)- and Western diet (WD)-fed mouse models of NAFLD. Acute liver injury was induced by carbon tetrachloride (CCl4). The role of PPARs on macrophage functionality was studied in isolated hepatic macrophages, bone marrow-derived macrophages stimulated with palmitic acid, and circulating monocytes from patients with NAFLD. Lanifibranor improved all histological features of steatohepatitis in CDAA-HFD-fed mice, including liver fibrosis, thereby combining and exceeding specific effects of the single PPAR agonists. Its potent anti-steatotic efficacy was confirmed in a 3D liver biochip model with primary cells. Infiltrating hepatic monocyte-derived macrophages were reduced following PPAR agonist administration, especially with lanifibranor, even after short-term treatment, paralleling improved steatosis and hepatitis. Lanifibranor similarly decreased steatosis, liver injury and monocyte infiltration in the WD model. In the acute CCl4 model, neither single nor pan-PPAR agonists directly affected monocyte recruitment. Hepatic macrophages isolated from WD-fed mice displayed a metabolically activated phenotype. Lanifibranor attenuated the accompanying inflammatory activation in both murine palmitic acid-stimulated bone marrow-derived macrophages, as well as patient-derived circulating monocytes, in a PPARδ-dependent fashion. Pan-PPAR agonists combine the beneficial effects of selective PPAR agonists and may counteract inflammation and disease progression more potently. PPARδ agonism and lanifibranor directly modulate macrophage activation, but not infiltration, thereby synergizing with beneficial metabolic effects of PPARα/γ agonists. Peroxisome proliferated-activated receptors (PPARs) are essential regulators of metabolism and inflammation. We demonstrated that the pan-PPAR agonist lanifibranor ameliorated all aspects of non-alcoholic fatty liver disease in independent experimental mouse models. Non-alcoholic fatty liver disease and fatty acids induce a specific polarization status in macrophages, which was altered by lanifibranor to increase expression of lipid handling genes, thereby decreasing inflammation. PPAR isoforms have differential therapeutic effects on fat-laden hepatocytes, activated hepatic stellate cells and inflammatory macrophages, supporting the clinical development of pan-PPAR agonists.

Evolution of a 4-Benzyloxy-benzylamino Chemotype to Provide Efficacious, Potent, and Isoform Selective PPARα Agonists as Leads for Retinal Disorders.

Peroxisome proliferator-activated receptor alpha (PPARα) is expressed in retinal Müller cells, endothelial cells, and in retinal pigment epithelium; agonism of PPARα with genetic or pharmacological tools ameliorates inflammation, vascular leakage, neurodegeneration, and neovascularization associated with retinal diseases in animal models. As such, PPARα is a promising drug target for diabetic retinopathy and age-related macular degeneration. Herein, we report proof-of-concept in vivo efficacy in an streptozotocin-induced vascular leakage model (rat) and preliminary pharmacokinetic assessment of a first-generation lead 4a (A91). Additionally, we present the design, synthesis, and evaluation of second-generation analogues, which led to the discovery of 4u and related compounds that reach cellular potencies <50 nM and exhibit >2,700-fold selectivity for PPARα over other PPAR isoforms. These studies identify a pipeline of candidates positioned for detailed PK/PD and pre-clinical evaluation.

Discovery of Novel Peroxisome Proliferator-Activated Receptor α (PPARα) Agonists by Virtual Screening and Biological Evaluation.

Nonalcoholic steatohepatitis (NASH) is one of the important causes of cirrhosis and hepatocellular carcinoma worldwide. PPARα is highly expressed in the liver and plays a critical role in hepatic lipid metabolism. Our analysis of the gene expression profiles in the liver of humanized mice treated with a PPARα agonist and NASH patients suggested that PPARα might be a potential target for NASH therapy. This promoted us to find novel PPARα agonists. The results of virtual screening and biological evaluation identified compound A-4 as a selective PPARα agonist. It significantly regulated the target genes of PPARα involved in fatty acid metabolism and inflammation, exhibiting cellular anti-inflammatory activity. The key residues involved in the binding between PPARα ligand-binding domain (LBD) and compound A-4 were revealed by molecular dynamics (MD) simulation and further experimentally validated by the mutation study. Together, compound A-4 was well characterized as a novel lead compound for developing potent and selective PPARα agonists.

Computational investigation reveals Picrasidine C as selective PPARα lead: binding pattern, selectivity mechanism and ADME/tox profile

Natural products and their derivatives have been recognized as an important source of therapeutic agents for many years. Previously we isolated a dimeric β-carboline-type alkaloid Picrasidine C from the root of Picrasma quassioides as subtype-selective peroxisome proliferator-activated receptor α (PPARα) agonist. In order to modify this natural product for better affinity and druggability, we investigated a series of properties exhibited by Picrasidine C, such as its binding mode with PPARα, the selectivity mechanism over PPARγ, as well as ADME/Tox profile through computational methods including sequence alignment, molecular docking, pharmacophore modeling and molecular dynamics simulations. The detailed information of binding pattern and affinity for Picrasidine C elucidated here will be valuable for chemical modification. Besides, the steric hindrance of residue Phe363 in PPARγ pocket was speculated as the main isoform selectivity mechanism for Picrasidine C, which would be helpful for the design of selective derivatives. ADME/Tox prediction was conducted to avoid potential undesirable pharmacokinetic properties for reducing the risk of failure. Finally, novel skeletons were derived from lead compound by core hopping method, validated through molecular dynamic simulations and MM-GBSA calculation. In short, the information obtained from computational strategy would be valuable for us to find more potent, safe and selective PPARα agonists during structural optimization.

The role of transient receptor potential vanilloid receptor 1 and peroxisome proliferator-activated receptors-α in mediating the antinociceptive effects of palmitoylethanolamine in rats.

Palmitoylethanolamine (PEA) is a ligand at peroxisome proliferator-activated receptors-α (PPARα), a nuclear receptor that has anti-inflammatory effects. Herein, complete Freund's adjuvant (CFA)-induced inflammatory pain model in rats and in-vitro calcium imaging studies were used to evaluate the mechanisms that underlie the antinociceptive effects of PEA, including modulating the activity of the transient receptor potential vanilloid receptor 1, which is a key receptor involved in the development of inflammatory pain. Adult male Sprague-Dawley rats (180-250 g) received subcutaneous injections of CFA (0.1 ml) into the plantar surface of the left hind paw. Von Frey filaments were used to determine the paw withdrawal threshold. PEA (50 µg), WY14643 (50 µg, a selective PPARα agonist) were injected into the plantar surface of the left hind paw at day 7 after CFA injection, and behavioral tests were repeated 6 h after drug administration. Rats were killed and dorsal root ganglia neurons were dissected and prepared for calcium imaging. Neurons were loaded with the calcium-sensitive ratiometric dye Fura-2AM. Changes in [Ca]i were measured as ratios of peak florescence at excitation wavelengths of 340 and 380 nm and expressed as a percentage of the KCl (60 mM) response. Both PEA and WY14643 significantly restored the paw withdrawal threshold in a PPARα-dependent fashion (P<0.01). Capsaicin of 15 nM produced 63.9±13.4% of KCl response. Preincubation of dorsal root ganglia neurons with PEA 6 h before stimulation with capsaicin, significantly reduce capsaicin-evoked calcium responses (42.9±6.4% of KCl response, n=54, P<0.001). In conclusion, modulating transient receptor potential vanilloid receptor 1 activity could provide the mechanism that underlies PEA antinociceptive effects observed in vivo.

Identification of novel PPARα/γ dual agonists by pharmacophore screening, docking analysis, ADMET prediction and molecular dynamics simulations

PPARα and PPARγ play an important role in regulating glucose and lipid metabolism. The single and selective PPARα or PPARγ agonists have caused several side effects such as edema, weight gain and cardiac failure. In the recent years, the dual PPARs agonist development has become a hot topic in the antidiabetic medicinal chemistry field. In this paper, the compound CHEMBL230490 were gained from CHEMBL database, by means of complex-based pharmacophore (CBP) virtual screening, molecular docking, ADMET prediction and molecular dynamics (MD) simulations. The compound CHEMBL230490 not only displayed higher binding scores and better binding modes with the active site of PPARα a/γ, but also had more favorable the pharmacokinetic properties and toxicity evaluated by ADMET prediction. The representative compound CHEMBL230490 was performed to MDs for studying a stable binding conformation. The results indicated that the CHEMBL230490 might be a potential antidiabetic lead compound. The research provided a valuable approach in developing novel PPARα/γ dual agonists for the treatment of type 2 diabetes mellitus (T2DM).

Selective modulator of peroxisome proliferator-activated receptor-α protects propionic acid induced autism-like phenotypes in rats

AimsThe present study investigated the neuropharmacological role of PPAR-α modulator, fenofibrate in postnatal-propionic acid induced symptomatology related with autism spectrum disorders (ASD) in Wistar rats. Main methodsThe propionic acid (250 mg/kg, p.o.) was administered to rats from postnatal 21st day to 23rd day to induce autism-related neurobehavioral and neurobiochemical alterations in rats. Then, rats were treated with fenofibrate (100 mg/kg and 200 mg/kg, orally) from postnatal 24th day till 48th day. The social behavior (three chambers social testing apparatus), repetitive behavior (Y-maze), locomotor activity (actophotometer), anxiety (elevated plus maze) and exploratory behavior (hole board test) were assessed. Biochemically, oxidative stress (thiobarbituric acid reactive species and reduced glutathione level) and neuroinflammation (interleukin-6, tumor necrosis factor-α and interleukin-10) were evaluated in the cerebellum, brainstem and prefrontal cortex of rats. Key findingsPropionic acid-treated rats showed social impairment, repetitive behavior, hyperlocomotion, anxiety and low exploratory activity. Also, these animals showed higher levels of oxidative stress (increased in thiobarbituric acid reactive species and decreased in reduced glutathione level) as well as inflammation (increased in interleukin-6, tumor necrosis factor-α and decreased in interleukin-10) and inflammation in aforementioned brain-regions. Treatment with fenofibrate significantly attenuated the propionic acid induced-social impairment, repetitive behavior, hyperactivity, anxiety and low exploratory activity. Furthermore, fenofibrate also reduced the oxidative stress and neuroinflammation in propionic acid-treated rats. SignificanceA selective PPAR-α agonist, fenofibrate provides neurobehavioral and neurobiochemical benefits in postnatal-propionic acid induced autism-related phenotype in rats. Thus, fenofibrate may further be studied for its possible benefits in ASD symptoms.

Cellular target engagement: a new paradigm in drug discovery.

Cellular target engagement: a new paradigm in drug discovery.

Targeted disruption of the Kcnj5 gene in the female mouse lowers aldosterone levels.

Aldosterone is released from adrenal zona glomerulosa (ZG) cells and plays an important role in Na and K homoeostasis. Mutations in the human inwardly rectifying K channel CNJ type (KCNJ) 5 (KCNJ5) gene encoding the G-coupled inwardly rectifying K channel 4 (GIRK4) cause abnormal aldosterone secretion and hypertension. To better understand the role of wild-type (WT) GIRK4 in regulating aldosterone release, we have looked at aldosterone secretion in a Kcnj5 knockout (KO) mouse. We found that female but not male KO mice have reduced aldosterone levels compared with WT female controls, but higher levels of aldosterone after angiotensin II (Ang-II) stimulation. These differences could not be explained by sex differences in aldosterone synthase (Cyp11B2) gene expression in the mouse adrenal. Using RNAseq analysis to compare WT and KO adrenals, we showed that females also have a much larger set of differentially expressed adrenal genes than males (395 compared with 7). Ingenuity Pathway Analysis (IPA) of this gene set suggested that peroxisome proliferator activated receptor (PPAR) nuclear receptors regulated aldosterone production and altered signalling in the female KO mouse, which could explain the reduced aldosterone secretion. We tested this hypothesis in H295R adrenal cells and showed that the selective PPARα agonist fenofibrate can stimulate aldosterone production and induce Cyp11b2. Dosing mice in vivo produced similar results. Together our data show that Kcnj5 is important for baseline aldosterone secretion, but its importance is sex-limited at least in the mouse. It also highlights a novel regulatory pathway for aldosterone secretion through PPARα that may have translational potential in human hyperaldosteronism.

The new-generation pan-peroxisome proliferator-activated receptor agonist IVA337 protects the liver from metabolic disorders and fibrosis.

IVA337 is a pan‐peroxisome proliferator‐activated receptor (PPAR) agonist with moderate and well‐balanced activity on the three PPAR isoforms (α, γ, δ). PPARs are regulators of lipid metabolism, inflammation, insulin resistance, and fibrogenesis. Different single or dual PPAR agonists have been investigated for their therapeutic potential in nonalcoholic steatohepatitis (NASH), a chronic liver condition in which steatosis coexists with necroinflammation, potentially leading to liver fibrosis and cirrhosis. Clinical results have demonstrated variable improvements of histologically assessed hepatic lesions depending on the profile of the tested drug, suggesting that concomitant activation of the three PPAR isoforms would translate into a more substantial therapeutic outcome in patients with NASH. We investigated the effects of IVA337 on several preclinical models reproducing the main metabolic and hepatic features associated with NASH. These models comprised a diet‐induced obesity model (high‐fat/high‐sucrose diet); a methionine‐ and choline‐deficient diet; the foz/foz model; the CCl4‐induced liver fibrosis model (prophylactic and therapeutic) and human primary hepatic stellate cells. IVA337 normalized insulin sensitivity while controlling body weight gain, adiposity index, and serum triglyceride increases; it decreased liver steatosis, inflammation, and ballooning. IVA337 demonstrated preventive and curative effects on fibrosis in the CCl4 model and inhibited proliferation and activation of human hepatic stellate cells, the key cells driving liver fibrogenesis in NASH. Moreover, IVA337 inhibited the expression of (pro)fibrotic and inflammasome genes while increasing the expression of β‐oxidation‐related and fatty acid desaturation‐related genes in both the methionine‐ and choline‐deficient diet and the foz/foz model. For all models, IVA337 displayed an antifibrotic efficacy superior to selective PPARα, PPARδ, or PPARγ agonists. Conclusion: The therapeutic potential of IVA337 for the treatment of patients with NASH is supported by our data. (Hepatology Communications 2017;1:524–537)

In vivo interactions between α7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α: Implication for nicotine dependence

Chronic tobacco use dramatically increases health burdens and financial costs. Limitations of current smoking cessation therapies indicate the need for improved molecular targets. The main addictive component of tobacco, nicotine, exerts its dependency effects via nicotinic acetylcholine receptors (nAChRs). Activation of the homomeric α7 nAChR reduces nicotine’s rewarding properties in conditioned place preference (CPP) test and i.v. self-administration models, but the mechanism underlying these effects is unknown. Recently, the nuclear receptor peroxisome proliferator-activated receptor type-α (PPARα) has been implicated as a downstream signaling target of the α7 nAChR in ventral tegmental area dopamine cells. The present study investigated PPARα as a possible mediator of the effect of α7 nAChR activation in nicotine dependence. Our results demonstrate the PPARα antagonist GW6471 blocks actions of the α7 nAChR agonist PNU282987 on nicotine reward in an unbiased CPP test in male ICR adult mice. These findings suggests that α7 nAChR activation attenuates nicotine CPP in a PPARα-dependent manner. To evaluate PPARα activation in nicotine dependence we used the selective and potent PPARα agonist, WY-14643 and the clinically used PPARα activator, fenofibrate, in nicotine CPP and we observed attenuation of nicotine preference, but fenofibrate was less potent. We also studied PPARα in nicotine dependence by evaluating its activation in nicotine withdrawal. WY-14643 reversed nicotine withdrawal signs whereas fenofibrate had modest efficacy. This suggests that PPARα plays a role in nicotine reward and withdrawal and that further studies are warranted to elucidate its function in mediating the effects of α7 nAChRs in nicotine dependence.

Fenofibrate Decreases Insulin Clearance and Insulin Secretion to Maintain Insulin Sensitivity

High fat diet reduces the expression of CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1), a transmembrane glycoprotein that promotes insulin clearance and down-regulates fatty acid synthase activity in the liver upon its phosphorylation by the insulin receptor. Because peroxisome proliferator-activated receptor α (PPARα) transcriptionally suppresses CEACAM1 expression, we herein examined whether high fat down-regulates CEACAM1 expression in a PPARα-dependent mechanism. By activating PPARα, the lipid-lowering drug fenofibrate reverses dyslipidemia and improves insulin sensitivity in type 2 diabetes in part by promoting fatty acid oxidation. Despite reducing glucose-stimulated insulin secretion, fenofibrate treatment does not result in insulin insufficiency. To examine whether this is mediated by a parallel decrease in CEACAM1-dependent hepatic insulin clearance pathways, we fed wild-type and Pparα-/- null mice a high fat diet supplemented with either fenofibrate or Wy14643, a selective PPARα agonist, and examined their effect on insulin metabolism and action. We demonstrated that the decrease in insulin secretion by fenofibrate and Wy14643 is accompanied by reduction in insulin clearance in wild-type but not Pparα-/- mice, thereby maintaining normoinsulinemia and insulin sensitivity despite continuous high fat intake. Intact insulin secretion in L-CC1 mice with protected hepatic insulin clearance and CEACAM1 levels provides in vivo evidence that insulin secretion responds to changes in insulin clearance to maintain physiologic insulin and glucose homeostasis. These results also emphasize the relevant role of hepatic insulin extraction in regulating insulin sensitivity.

Identification of dual PPARα/γ agonists and their effects on lipid metabolism

The three peroxisome proliferator-activated receptor (PPAR) isoforms; PPARα, PPARγ and PPARδ, play central roles in lipid metabolism and glucose homeostasis. Dual PPARα/γ agonists, which stimulate both PPARα and PPARγ isoforms to similar extents, are gaining popularity as it is believed that they are able to ameliorate the unwanted side effects of selective PPARα and PPARγ agonists; and may also be used to treat dyslipidemia and type 2 diabetes mellitus simultaneously. In this study, virtual screening of natural product libraries, using both structure-based and ligand-based drug discovery approaches, identified ten potential dual PPARα/γ agonist lead compounds (9–13 and 16–20). In vitro assays confirmed these compounds to show no statistically significant toxicity to cells, with the exception of compound 12 which inhibited cell growth to 74.5%±3.5 and 54.1%±3.7 at 50μM and 100μM, respectively. In support of their potential as dual PPARα/γ agonists, all ten compounds upregulated the expression of cholesterol transporters ABCA1 and ABCG1 in THP-1 macrophages, with indoline derivative 16 producing the greatest elevation (2.3-fold; 3.3-fold, respectively). Furthermore, comparable to the activity of established PPARα and PPARγ agonists, compound 16 stimulated triacylglycerol accumulation during 3T3-L1 adipocyte differentiation as well as fatty acid β-oxidation in HuH7 hepatocytes.