PPARα Agonist Research Articles

Non-alcoholic fatty liver disease in type 2 diabetes: Emerging evidence of benefit of peroxisome proliferator-activated receptors agonists and incretin-based therapies.

Nonalcoholic fatty liver disease (NAFLD) is a global epidemic, affecting more than half of the people living with type 2 diabetes (T2D). The relationship between NAFLD and T2D is bidirectional and the presence of one perpetuates the other, which significantly increases the hepatic as well as extrahepatic complications. Until recently, there was no approved pharmacological treatment for NAFLD/ nonalcoholic steatohepatitits (NASH). However, there is evidence that drugs used for diabetes may have beneficial effects on NAFLD. Insulin sensitizers acting through peroxisome proliferator-activated receptor (PPAR) modulation act on multiple levels of NAFLD pathogenesis. Pioglitazone (PPARγ agonist) and saroglitazar (PPARα/γ agonist) are particularly beneficial and recommended by several authoritative bodies for treating NAFLD in T2D, although data on biopsy-proven NASH are lacking with the latter. Initial data on elafibanor (PPAR α/δ agonist) and Lanifibranor (pan PPAR agonist) are promising. On the other hand, incretin therapies based on glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RA) and dual- and triple-hormone receptor co-agonists reported impressive weight loss and may have anti-inflammatory and antifibrotic properties. GLP-1 RAs have shown beneficial effects on NAFLD/NASH and more studies on potential direct effects on liver function by dual- and triple-agonists are required. Furthermore, the long-term safety of these therapies in NAFLD needs to be established. Collaborative efforts among healthcare providers such as primary care doctors, hepatologists, and endocrinologists are warranted for selecting patients for the best possible management of NAFLD in T2D.

Topical and oral peroxisome proliferator-activated receptor-α agonist ameliorates diabetic corneal neuropathy

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.

Regulation of hepatic xenosensor function by HNF4alpha.

Nuclear receptors such as constitutive androstane receptor (CAR), pregnane X receptor (PXR), and peroxisome proliferator-activated receptor-alpha (PPARα), and transcription factors with nuclear receptor type activity such as aryl hydrocarbon receptor (AhR) function as xenobiotic sensors. Hepatocyte nuclear factor 4alpha (HNF4α) is a highly conserved orphan nuclear receptor essential for liver function. We tested the hypothesis that HNF4α is essential for the function of these 4 major xenosensors. Wild-type (WT) and hepatocyte-specific Hnf4a null (HNF4α-KO) mice were treated with the mouse-specific activators of AhR (TCDD, 30 µg/kg), CAR (TCPOBOP, 2.5 µg/g), PXR, (PCN, 100 µg/g), and PPARα (WY-14643, 1 mg/kg). Blood and liver tissue samples were collected to study receptor activation. TCDD (AhR agonist) treatment did not affect the liver-to-body weight ratio (LW/BW) in either WT or HNF4α-KO mice. Further, TCDD activated AhR in both WT and HNF4α-KO mice, confirmed by increase in expression of AhR target genes. TCPOBOP (CAR agonist) significantly increased the LW/BW ratio and CAR target gene expression in WT mice, but not in HNF4α-KO mice. PCN (a mouse PXR agonist) significantly increased LW/BW ratio in both WT and HNF4α-KO mice however, failed to induce PXR target genes in HNF4α-KO mice. The treatment of WY-14643 (PPARα agonist) increased LW/BW ratio and PPARα target gene expression in WT mice but not in HNF4α-KO mice. Together, these data indicate that the function of CAR, PXR, and PPARα but not of AhR was disrupted in HNF4α-KO mice. These results demonstrate that HNF4α function is critical for the activation of hepatic xenosensors, which are critical for toxicological responses.

ACAD9 treatment with bezafibrate and nicotinamide riboside temporarily stabilizes cardiomyopathy and lactic acidosis

Pathogenic ACAD9 variants cause complex I deficiency. Patients presenting in infancy unresponsive to riboflavin have high mortality. A six-month-old infant presented with riboflavin unresponsive lactic acidosis and life-threatening cardiomyopathy. Treatment with high dose bezafibrate and nicotinamide riboside resulted in marked clinical improvement including reduced lactate and NT-pro-brain type natriuretic peptide levels, with stabilized echocardiographic measures. After a long stable period, the child succumbed from cardiac failure with infection at 10.5 months. Therapy was well tolerated. Peak bezafibrate levels exceeded its EC50. The clinical improvement with this treatment illustrates its potential, but weak PPAR agonist activity of bezafibrate limited its efficacy.

Common alterations in parallel metabolomic profiling of serum and spinal cord and mechanistic studies on neuropathic pain following PPARα administration

Neuropathic pain (NP) is usually treated with analgesics and symptomatic therapy with poor efficacy and numerous side effects, highlighting the urgent need for effective treatment strategies. Recent studies have reported an important role for peroxisome proliferator-activated receptor alpha (PPARα) in regulating metabolism as well as inflammatory responses. Through pain behavioral assessment, we found that activation of PPARα prevented chronic constriction injury (CCI)-induced mechanical allodynia and thermal hyperalgesia. In addition, PPARα ameliorated inflammatory cell infiltration at the injury site and decreased microglial activation, NOD-like receptor protein 3 (NLRP3) inflammasome production, and spinal dendritic spine density, as well as improved serum and spinal cord metabolic levels in mice. Administration of PPARα antagonists eliminates the analgesic effect of PPARα agonists. PPARα relieves NP by inhibiting neuroinflammation and functional synaptic plasticity as well as modulating metabolic mechanisms, suggesting that PPARα may be a potential molecular target for NP alleviation. However, the effects of PPARα on neuroinflammation and synaptic plasticity should be further explored.

The reversal of PXR or PPARα activation-induced hepatomegaly

The activation of pregnane X receptor (PXR) or peroxisome proliferator-activated receptor α (PPARα) can induce liver enlargement. Recently, we reported that PXR or PPARα activation-induced hepatomegaly depends on yes-associated protein (YAP) signaling and is characterized by hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. However, it remains unclear whether PXR or PPARα activation-induced hepatomegaly can be reversed after the withdrawal of their agonists. In this study, we investigated the regression of enlarged liver to normal size following the withdrawal of PCN or WY-14643 (typical agonists of mouse PXR or PPARα) in C57BL/6 mice. The immunohistochemistry analysis of CTNNB1 and KI67 showed a reversal of hepatocyte size and a decrease in hepatocyte proliferation after the withdrawal of agonists. In details, the expression of PXR or PPARα downstream proteins (CYP3A11, CYP2B10, ACOX1, and CYP4A) and the expression of proliferation-related proteins (CCNA1, CCND1, and PCNA) returned to the normal levels. Furthermore, YAP and its downstream proteins (CTGF, CYR61, and ANKRD1) also restored to the normal states, which was consistent with the change in liver size. These findings demonstrate the reversibility of PXR or PPARα activation-induced hepatomegaly and provide new data for the safety of PXR and PPARα as drug targets.

Retinal ischemic diseases and promising therapeutic molecular targets.

Retinal ischemia is a fundamental pathologic condition associated with retinal vascular occlusion, glaucoma, diabetic retinopathy, age-related macular degeneration, and other eye diseases. Extensive inflammation, redox imbalance, apoptosis, and abnormal vascular formation in retinal ischemia could lead to visual impairments. Developing or finding effective treatments is urgently needed to protect the eye against retinal ischemia and related damage. To address the demand, we have searched for promising therapeutic molecular targets in the eye (e.g., hypoxia-inducible factor [HIF], peroxisome proliferator-activated receptor-alpha [PPARα], and nicotinamide adenine dinucleotide [NAD+]), and found that modulations of each molecular target might protect the eye against retinal ischemic damage in terms of complex pathologic mechanisms. In the current article, we review and update the therapeutic evidence of modulation of HIF, PPARα, or NAD+ and discuss future directions for developing promising drugs based on these molecular targets. This summary urges research to obtain more solid evidence of each molecular target in retinal ischemic diseases.

MASLD/MASH and type 2 diabetes: Two sides of the same coin? From single PPAR to pan-PPAR agonists

Type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), mainly related to nutrition and lack of physical activity, are both very common conditions, share several disease pathways and clinical manifestations, and increasingly co-occur with disease progression. Insulin resistance is an upstream node in the biology of both conditions and triggers liver parenchymal injury, inflammation and fibrosis. Peroxisome proliferator-activated receptor (PPAR) nuclear transcription factors are master regulators of energy homeostasis − insulin signaling in liver, adipose and skeletal muscle tissue − and affect immune and fibrogenesis pathways. Among distinct yet overlapping effects, PPARα regulates lipid metabolism and energy expenditure, PPARβ/δ has anti-inflammatory effects and increases glucose uptake by skeletal muscle, while PPARγ improves insulin sensitivity and exerts direct antifibrotic effects on hepatic stellate cells. Together PPARs thus represent pharmacological targets across the entire biology of MASH. Single PPAR agonists are approved for hypertriglyceridemia (PPARα) and T2D (PPARγ), but these, as well as dual PPAR agonists, have shown mixed results as anti-MASH treatments in clinical trials. Agonists of all three PPAR isoforms have the potential to improve the full disease spectrum from insulin resistance to fibrosis, and correspondingly to improve cardiometabolic and hepatic health, as has been shown (phase II data) with the pan-PPAR agonist lanifibranor.

Regulation of Renal Cortical PPAR-alpha and Downstream Targets by Sodium Glucose Cotransporter, Type 2 Inhibition (SGLT2i) in High-Fat Fed Mice

SGLT2i has been shown to be protective of renal function and health in type 2 diabetes by unclear means. Recently we reported that empagliflozin (EMPA) treatment of mice on a high-fat diet (HFD) led to marked changes in the renal cortical lipidome, including significant upregulation of many carnitine species (11 species > 35% increased, all p < 0.05). Carnitines are critical in the oxidation of long-chain fatty acids by increasing their uptake into the mitochondria. The mechanism underlying this upregulation was unclear, but the peroxisome proliferator activated receptor, subtype alpha (PPARα) has been demonstrated to upregulate carnitines in other tissues. To the test the impact of EMPA (E) or control (C) treatment on renal cortical PPARα and downstream targets, male (M) and female (F) C57Bl6 mice were treated with HFD (60% by weight) ± EMPA (100 mg/kg·diet) for 12 weeks. EMPA caused a reduction in final body weight (20%) only in females. No differences were observed in final kidney weights (n = 16-18/group). Glomerular filtration rate (GFR) measured by FITC-sinistrin clearance showed a trend (p = 0.052 two-way ANOVA) for an increase by EMPA (mean ± sem, ml/min, n = 5-9): MC- 246 ± 13; ME- 291 ± 5; FC- 252 ± 13; and FE- 275 ± 36. Western blotting of cortex homogenates revealed a modest, insignificant rise in PPARα, itself with EMPA, and a higher overall abundance in females (p = 0.024 for sex, mean band density, % MC): MC-100 ± 14; ME- 108 ±11; FC- 123± 12, FE- 151± 18. Fibroblast growth factor 21 (FGF21) is a reported target of PPARα, and has been shown to be increased in liver in response to treatment with a PPARα agonist. However, FGF21 is also increased compensatorily in metabolic stress conditions, e.g., obesity. We found EMPA treatment substantially reduced circulating FGF21 levels in M, while F levels were low regardless of treatment (ng/ml): MC-3.28 ± 1.32; ME- 0.07 ± 0.027; FC- 0.19 ± 0.08, FE- 0.17 ± 0.08 (p = 0.031, 0.044, and 0.033, for treatment, sex, and interaction, respectively). FGF21 levels in liver, site of most production (measured in males only) was likewise reduced by EMPA (84%, p = 0.029, Mann-Whitney test). In contrast, no significant differences were found for renal cortical FGF21 levels. Previously, we showed PPARα whole-body knockout mice had higher renal expression of Na+K+ATPase, which was associated with higher blood pressure. Western blotting of EMPA-treated mice showed the α-1 subunit of Na+K+ATPase, a surrogate marker of proximal tubule transport activity, was significantly increased in the kidney cortex of EMPA-treated mice (band density % MC): MC-100 ± 26; ME- 145 ± 25; FC- 99 ± 22, FE- 175 ± 21 (p = 0.54, 0.016, and 0.52, for treatment, sex, and interaction, respectively). This was not associated with higher blood pressure in EMPA-treated mice, as measured by tail-cuff. Taken together, these findings do not suggest an overall increase in activity of PPARα in kidney or systemically (in liver) with EMPA. The upregulation of carnitine species in kidney may have resulted from an alternative mechanism. Additional studies are warranted to gauge the role of PPARα activation, emanating from a relatively fasted state, with SGLT2 inhibition, in the kidney and in regard to whole body metabolism. Supported by GHUCCTS (Howard and Georgetown, UL1TR001409) pilot award to CE. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Macrophage Targeted Dendrimer-Tesaglitazar Therapy for Atherosclerosis

Background: Atherosclerosis is a leading contributor to cardiovascular disease, the number one cause of death globally. Although atherosclerosis is clearly a multicellular disease that also affects endothelial cells as well as smooth muscle cells of arteries, it is increasingly recognized as an inflammatory disease. Our goal is to determine if targeting immune cells implicated in atherosclerosis can halt plaque accumulation and resulting derangement of vascular cells in the aorta. Peroxisome proliferator activated receptors (PPARs) within macrophages present a promising therapeutic target as PPAR-α and PPAR-γ agonists have been shown to improve lipid metabolism and inhibit macrophage foam cell formation. However, due to high doses required and associated side effects, clinical translation was halted. We target anti-atherogenic pathways in immune cells using the novel treatment D-Tesa, a dendrimer conjugate of a dual PPAR-α/γ agonist, Tesaglitazar. Methods: 25-week-old, male, apolipoprotein E knockout (ApoE−/−) mice were fed high fat diet (HFD) for 16 weeks to induce atherosclerosis and randomized into two groups: 1) treatment group: D-Tesa for 6 weeks (20μg/kg twice weekly by oral gavage and 2) untreated group. HFD was continued for the duration of the study. Pulse wave velocity (PWV: Doppler), blood pressure (BP: tail cuff on trained, conscious mice), and body weight were monitored. Dendrimer mediated delivery of drug payload to plaque macrophages was studied using D-Cy5, a fluorescently labeled dendrimer, in an atherosclerotic mouse. Aortas were isolated and used for vasoreactivity studies and western blot analysis. THP-1 cell derived foam cells were used to study D-Tesa’s mechanism of action in vitro. Results: Immunofluorescence staining and confocal microscopy revealed that D-Cy5 localized in macrophages within the atherosclerotic plaque in ApoE−/− mice on HFD, indicating that the dendrimer can deliver drugs specifically into the plaque. D-Tesa slowed plaque progression, preserved endothelial function, and decreased arterial stiffness. BP was similar and unchanged between groups. D-Tesa surprisingly decreased body weight, which was the opposite effect observed from the free drug in clinical trials. Western blotting of aorta revealed that D-Tesa treated mice experienced an upregulation of PPAR-α, PPAR-γ, and ABCA1. The in vitro studies with THP-1 derived foam cells confirmed the upregulation of the cholesterol efflux pathway and anti-inflammatory benefit of D-Tesa. Conclusion: D-Tesa offers a novel therapy to ameliorate multiple damaging consequences of atherosclerosis on the cardiovascular system including improvements in plaque burden, endothelial function, arterial stiffness, and body weight in an ApoE−/− model of atherosclerosis. Excitingly, these effects were seen at 2-15 times lower doses despite continued HFD than those reported in literature with a combination of free Tesa and low-fat diet. Thus, D-Tesa offers great translational relevance because of potential reduction in negative side effects and higher patient benefit due to noted lack of compliance with dietary changes in the clinic. Further research is ongoing to evaluate sex differences, dose response, and long-term effects of this highly promising therapy. This work was supported by a NHLBI grant R01HL148112 01 (L.S.) and the Traystman Endowment (S.K.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Assessing the ability of dihydrosterculic acid to activate PPARα

Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor associated with the expression of specific target genes involved in fatty acid β-oxidation. Activation of PPARα could potentially be utilized to treat diseases associated with the accumulation of hepatic lipids such as non-alcoholic fatty liver disease (NAFLD), which currently impacts approximately 25% of the world’s population. At present, a class of synthetic ligands called fibrates can be prescribed to help manage NAFLD but are weak agonists for PPARα and therefore have limited effcacy. Consequently, alternative ligands for PPARα must be established and no natural endogenous ligands have been conclusively identified. This study expands on our previous work and aims to identify the direct effects of dihydrosterculic acid (DHSA), a cyclopropyl fatty acid found in cottonseed oil (CSO), on PPARα activity. To identify downstream effects of DHSA, male mice were placed on a CSO- (DHSA-containing) or isocaloric oil-enriched diet for 6 weeks and tissues were sent for genome-wide RNA sequencing analysis. CSO-fed mice demonstrated increased PPARα gene expression in the liver and concomitant decreased triglyceride in plasma (-75.1±11.5 milligrams/deciliter (mg/dL); p<0.01) and liver (-86.7±71.7 mg/gram (g) protein; p=0.1) and decreased free fatty acid in liver (-16.5±3.4 micromolar (μM)/g protein; p<0.01) relative to the oil-enriched control diet. Confirmational tissue analysis of liver samples show an increase in PPARα target gene expression in the DHSA containing groups compared to control diet groups, indicating that DHSA could potentially serve as an endogenous ligand for PPARα to increase its transcriptional activity to increase fat oxidation. To further test this hypothesis, female PPARα knockout mice were fed a DHSA containing diet or control diet for 4 weeks (n=8). Following the 4-week period, the chow-fed wild type females gained more weight (1.3±0.6 g; p<0.05) than the PPARα knockout mice. Otherwise, there were no significant differences in body weight or food intake between diets or genotypes. Additional in vitro studies show increased PPARα target gene expression following treatments with DHSA, specifically for CPT1a (2.7±0.2 fold increase; p<0.01), ACOX1 (1.3±0.1 fold increase; p<0.05), and ACADVL (1.6±0.1 fold increase, p<0.01), which encode key enzymes in lipid oxidation pathways. SCD1, the rate limiting enzyme in lipogenesis, was also downregulated (0.5±0.03 fold decrease, p<0.01) in response to a 24-hour treatment with DHSA indicating a reduction in endogenous lipogenesis. From these results, we believe that DHSA could function through a PPARα-dependent mechanism. Further analysis of the tissues collected from the PPARα knockout mouse model will aid in determining the mechanism of DHSA as well as identifying its potential for the treatment of excess lipid accumulation. This project is funded by Cotton Incorporated. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Synthesis of a new 2-prenylated quinoline as potential drug for metabolic syndrome with pan-PPAR activity and anti-inflammatory effects

We have previously reported the total synthesis and structure–activity relationships (SAR) of 2-prenylated benzopyrans with PPAR agonist activity. Herein, we have described the synthesis and PPAR activity of 2-prenylated benzopyrans and 2-prenylated quinolines. The benzopyran nucleus was generated via enamine-catalyzed Kabbe condensation, and the quinoline nucleus via Friedländer condensation. Results demonstrated that both benzopyran (5a) and quinoline (4b) derivatives bearing a γ,δ-unsaturated ester displayed a pan-PPAR agonism. They were full PPARα agonists, but showed different preferences for PPARγ and PPARβ/δ activation. It was noteworthy that quinoline 4b displayed full hPPARα activation (2-fold than WY-14,643), weak PPARβ/δ and partial PPARγ activation. In addition, quinoline 4b showed anti-inflammatory effects on macrophages by reducing LPS-induced expression of both MCP-1 and IL-6. Therefore, 4b emerges as a first-in-class promising hit compound for the development of potential therapeutics aimed at treating metabolic syndrome, metabolic dysfunction-associated fatty liver disease (MAFLD), and its associated cardiovascular comorbidities.

Cellular senescence-Related genes define the immune microenvironment and molecular characteristics in severe asthma patients

Recent studies have shown that cellular senescence is involved in the pathogenesis of severe asthma (SA). The objective of this study was to investigate the role of cellular senescence-related genes (CSGs) in the pathogenesis of SA. Here, 54 differentially expressed CSGs were identified in SA patients compared to healthy control individuals. Among the 54 differentially expressed CSGs, 3 CSGs (ETS2, ETS1 and AURKA) were screened using the LASSO regression analysis and logistic regression analysis to establish the CSG-based prediction model to predict severe asthma. Moreover, we found that the protein expression levels of ETS2, ETS1 and AURKA were increased in the severe asthma mouse model. Then, two distinct senescence subtypes of SA with distinct immune microenvironments and molecular biological characteristics were identified. Cluster 1 was characterized by increased infiltration of immature dendritic cells, regulatory T cells, and other cells. Cluster 2 was characterized by increased infiltration levels of eosinophils, neutrophils, and other cells. The molecular biological characteristics of Cluster 1 included aerobic respiration and oxidative phosphorylation, whereas the molecular biological characteristics of Cluster 2 included activation of the immune response and immune receptor activity. Then, we established an Random Forest model to predict the senescence subtypes of SA to guide treatment. Finally, potential drugs were searched for each senescence subgroup of SA patients via the Connectivity Map database. A peroxisome proliferator-activated receptor agonist may be a potential therapeutic drug for patients in Cluster 1, whereas a tachykinin antagonist may be a potential therapeutic drug for patients in Cluster 2. In summary, CSGs are likely involved in the pathogenesis of SA, which may lead to new therapeutic options for SA patients.

PPAR agonists as add-on treatment with metformin in management of type 2 diabetes: a systematic review and meta-analysis.

The combination of metformin and the peroxisome proliferator-activated receptors (PPAR) agonists offers a promising avenue for managing type 2 diabetes (T2D) through their potential complementary mechanisms of action. The results from randomized controlled trials (RCT) assessing the efficacy of PPAR agonists plus metformin versus metformin alone in T2D are inconsistent, which prompted the conduct of the systematic review and meta-analysis. We searched MEDLINE and EMBASE from inception (1966) to March 2023 to identify all RCTs comparing any PPAR agonists plus metformin versus metformin alone in T2D. Categorical variables were summarized as relative risk along with 95% confidence interval (CI). Twenty RCTs enrolling a total of 6058 patients met the inclusion criteria. The certainty of evidence ranged from moderate to very low. Pooled results show that using PPAR agonist plus metformin, as compared to metformin alone, results in lower concentrations of fasting glucose [MD = - 22.07mg/dl (95% CI - 27.17, - 16.97), HbA1c [MD = - 0.53% (95% CI - 0.67, - 0.38)], HOMA-IR [MD = - 1.26 (95% CI - 2.16, - 0.37)], and fasting insulin [MD = - 19.83pmol/L (95% CI - 29.54, - 10.13)] without significant increase in any adverse events. Thus, synthesized evidence from RCTs demonstrates the beneficial effects of PPAR agonist add-on treatment versus metformin alone in T2D patients. In particular, novel dual PPARα/γ agonist (tesaglitazar) demonstrate efficacy in improving glycaemic and lipid concentrations, so further RCTs should be performed to elucidate the long-term outcomes and safety profile of these novel combined and personalized therapeutic strategies in the management of T2D.PROSPERO registration no. CRD42023412603.

Combining fecal 16 S rRNA sequencing and spinal cord metabolomics analysis to explain the modulatory effect of PPARα on neuropathic pain

BackgroundExisting evidence suggests that the composition of the gut microbiota is associated with neuropathic pain (NP), but the mechanistic link is elusive. Peroxisome proliferator-activated receptor α (PPARα) has been shown to be a pharmacological target for the treatment of metabolic disorders, and its expression is also involved in inflammatory regulation. The aim of this study was to investigate the important modulatory effects of PPARα on gut microbiota and spinal cord metabolites in mice subjected to chronic constriction injury. MethodsWe analyzed fecal microbiota and spinal cord metabolic alterations in mice from the sham, CCI, GW7647 (PPARα agonist) and GW6471 (PPARα antagonist) groups by 16 S rRNA amplicon sequencing and untargeted metabolomics analysis. On this basis, the intestinal microbiota and metabolites that were significantly altered between treatment groups were analyzed in a combined multiomics analysis. We also investigated the effect of PPARα on the polarization fractionation of spinal microglia. ResultsPPARα agonist significantly reduce paw withdrawal threshold and paw withdrawal thermal latency, while PPARα antagonist significantly increase paw withdrawal threshold and paw withdrawal thermal latency. 16 S rRNA gene sequencing showed that intraperitoneal injection of GW7647 or GW6471 significantly altered the abundance, homogeneity and composition of the gut microbiome. Analysis of the spinal cord metabolome showed that the levels of spinal cord metabolites were shifted after exposure to GW7647 or GW6471. Alterations in the composition of gut microbiota were significantly associated with the abundance of various spinal cord metabolites. The abundance of Licheniformes showed a significant positive correlation with nicotinamide, benzimidazole, eicosanoids, and pyridine abundance. Immunofluorescence results showed that intraperitoneal injection of GW7647 or GW6471 altered microglial activation and polarization levels. ConclusionOur study shows that PPARα can promote M2-type microglia polarization, as well as alter gut microbiota and metabolites in CCI mice. This study enhances our understanding of the mechanism of PPARα in the treatment of neuropathic pain.

Furan-based chalcone protects β-cell damage and improves glucose uptake in alloxan-induced zebrafish diabetic model via influencing Peroxisome Proliferator-Activated Receptor agonists (PPAR-γ) signaling

Diabetes mellitus, a major global health concern, is emerging as the primary human disease in the twenty-first century, with beta cell damage and dysfunction playing a critical role, particularly in type 2 diabetes. Inflammation and oxidative stress are critical in beta cell damage associated with type 2 diabetes. Current anti-diabetic drugs frequently fail to achieve intended efficacy and are associated with side effects, necessitating novel treatments that target the underlying pathophysiology. Chalcones have gained popularity due to their varied biological activity. In this study, we use an alloxan-induced beta cell damage zebrafish model to evaluate the potential anti-inflammatory and beta cell protective properties of DKO3 ((E)-1-(5-methylfuran-2-yl)-3-(3-nitrophenyl) prop-2-en-1-one), a synthetic chalcone. DKO3 exhibits dose-dependent anti-inflammatory and α-glucosidase activity in vitro. DKO3 reduced oxidative stress, restored antioxidant enzyme levels, decreased lipid peroxidation and cellular damage, inhibited cellular apoptosis, and regulated proinflammatory cytokine levels. It prevented alloxan-induced beta cell damage, increased PPAR-γ expression, and influenced insulin-sensitive genes such as SIRT1, GLUT2, GSK3, and INSA. These findings underscore DKO3's potential therapeutic utility in managing diabetes and related inflammatory conditions.

Comparison of transcriptomic profiles between HFPO-DA and prototypical PPARα, PPARγ, and cytotoxic agents in mouse, rat, and pooled human hepatocytes.

Like many per- or polyfluorinated alkyl substances (PFAS), toxicity studies with HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate), a short-chain PFAS used in the manufacture of some types of fluorinated polymers, indicate that the liver is the primary target of toxicity in rodents following oral exposure. Although the current weight of evidence supports the PPARα mode of action (MOA) for liver effects in HFPO-DA-exposed mice, alternate MOAs have also been hypothesized including PPARγ or cytotoxicity. To further evaluate the MOA for HFPO-DA in rodent liver, transcriptomic analyses were conducted on samples from primary mouse, rat, and pooled human hepatocytes treated for 12, 24, or 72 h with various concentrations of HFPO-DA, or agonists of PPARα (GW7647), PPARγ (rosiglitazone), or cytotoxic agents (ie, acetaminophen or d-galactosamine). Concordance analyses of enriched pathways across chemicals within each species demonstrated the greatest concordance between HFPO-DA and PPARα agonist GW7647-treated hepatocytes compared with the other chemicals evaluated. These findings were supported by benchmark concentration modeling and predicted upstream regulator results. In addition, transcriptomic analyses across species demonstrated a greater transcriptomic response in rodent hepatocytes treated with HFPO-DA or agonists of PPARα or PPARγ, indicating rodent hepatocytes are more sensitive to HFPO-DA or PPARα/γ agonist treatment. These results are consistent with previously published transcriptomic analyses and further support that liver effects in HFPO-DA-exposed rodents are mediated through rodent-specific PPARα signaling mechanisms as part of the MOA for PPARα activator-induced rodent hepatocarcinogenesis. Thus, effects observed in mouse liver are not appropriate endpoints for toxicity value development for HFPO-DA in human health risk assessment.

Study on the Mechanism of Estrogen Regulating Endometrial Fibrosis After Mechanical Injury Via MIR-21-5P/PPARΑ/FAO Axis.

Intrauterine adhesion (IUA) caused by endometrial mechanical injury has been found as a substantial risk factor for female infertility (e.g., induced abortion). Estrogen is a classic drug for the repair of endometrial injury, but its action mechanism in the clinical application of endometrial fibrosis is still unclear. To explore the specific action mechanism of estrogen treatment on IUA. The IUA model in vivo and the isolated endometrial stromal cells (ESCs) model in vitro were built. Then CCK8 assay, Real-Time PCR, Western Blot and Dual- Luciferase Reporter Gene assay were applied to determine the targeting action of estrogen on ESCs. It was found that 17β-estradiol inhibited fibrosis of ESCs by down-regulating miR-21-5p level and activating PPARα signaling. Mechanistically, miR-21-5p significantly reduced the inhibitory effect of 17β-estradiol on fibrotic ESCs (ESCs-F) and its maker protein (e.g., α-SMA, collagen I, and fibronectin), where targeting to PPARα 3'- UTR and blocked its activation and transcription, thus lowering expressions of fatty acid oxidation (FAO) associated key enzyme, provoking fatty accumulation and reactive oxygen species (ROS) production, resulting in endometrial fibrosis. Nevertheless, the PPARα agonist caffeic acid counteracted the facilitation action of miR-21-5p on ESCs-F, which is consistent with the efficacy of estrogen intervention. In brief, the above findings revealed that the miR-21-5p/PPARα signal axis played an important role in the fibrosis of endometrial mechanical injury and suggested that estrogen might be a promising agent for its progression.

Fenofibrate-promoted hepatomegaly and liver regeneration are PPARα-dependent and partially related to the YAP pathway

Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely prescribed for hyperlipidemia management. Recent studies also showed that it has therapeutic potential in various liver diseases. However, its effects on hepatomegaly and liver regeneration and the involved mechanisms remain unclear. Here, the study showed that fenofibrate significantly promoted liver enlargement and regeneration post-partial hepatectomy in mice, which was dependent on hepatocyte-expressed PPARα. Yes-associated protein (YAP) is pivotal in manipulating liver growth and regeneration. We further identified that fenofibrate activated YAP signaling by suppressing its K48-linked ubiquitination, promoting its K63-linked ubiquitination, and enhancing the interaction and transcriptional activity of the YAP–TEAD complex. Pharmacological inhibition of YAP–TEAD interaction using verteporfin or suppression of YAP using AAV Yap shRNA in mice significantly attenuated fenofibrate-induced hepatomegaly. Other factors, such as MYC, KRT23, RAS, and RHOA, might also participate in fenofibrate-promoted hepatomegaly and liver regeneration. These studies demonstrate that fenofibrate-promoted liver enlargement and regeneration are PPARα-dependent and partially through activating the YAP signaling, with clinical implications of fenofibrate as a novel therapeutic agent for promoting liver regeneration.

Azoles display promising anticonvulsant effects through possible PPAR-α activation

Azoles such as nafimidone, denzimol and loreclezole are known for their clinical efficacy against epilepsy, and loreclezole acts by potentiating γ-aminobutyric acid (GABA)-ergic currents. In the current study, we report a series of azole derivatives in alcohol ester and oxime ester structure showing promising anticonvulsant effects in 6 Hz and maximal electro shock (MES) models with minimal toxicity. The most promising of the series, 5f, was active in both 6 Hz and MES tests with a median effective dose (ED50) of 118.92 mg/kg in 6 Hz test and a median toxic dose (TD50) twice as high in mice. The compounds were predicted druglike and blood–brain barrier (BBB) penetrant in silico. Contrary to what was expected, the compounds showed no in vitro affinity to GABAA receptors (GABAARs) in radioligand binding assays; however, they were found structurally similar to peroxisome proliferator-activated receptors alpha (PPAR-α) agonists and predicted to show high affinity and agonist-like binding to PPAR-α in molecular docking studies. As a result, 5f emerged as a safe azole anticonvulsant with a wide therapeutic window and possible action through PPAR-α activation.