ABSTRACT
BACKGROUND: Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality, but there are no therapeutic targets and modalities to prevent ALD-related liver fibrosis. Peroxisome proliferator activated receptor (PPAR) α and δ play a key role in lipid metabolism and intestinal barrier homeostasis, which are major contributors to the pathological progression of ALD. Meanwhile, elafibranor (EFN), which is a dual PPARα and PPARδ agonist, has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease and primary biliary cholangitis. However, the benefits of EFN for ALD treatment is unknown. AIM: To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse model. METHODS: ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol (EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly (1 mL/kg) for 8 weeks. EFN (3 and 10 mg/kg/day) was orally administered during the experimental period. Histological and molecular analyses were performed to assess the effect of EFN on steatohepatitis, fibrosis, and intestinal barrier integrity. The EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based assays. RESULTS: The hepatic steatosis, apoptosis, and fibrosis in the ALD mice model were significantly attenuated by EFN treatment. EFN promoted lipolysis and ß-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells, primarily through PPARα activation. Moreover, EFN inhibited the Kupffer cell-mediated inflammatory response, with blunted hepatic exposure to lipopolysaccharide (LPS) and toll like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling. EFN improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory responses. The protective effect on intestinal barrier function in the EtOH-stimulated Caco-2 cells was predominantly mediated by PPARδ activation. CONCLUSION: EFN reduced ALD-related fibrosis by inhibiting lipid accumulation and apoptosis, enhancing hepatocyte autophagic and antioxidant capacities, and suppressing LPS/TLR4/NF-κB-mediated inflammatory responses by restoring intestinal barrier function.
Subject(s)
Chalcones , Disease Models, Animal , Intestinal Mucosa , Liver Cirrhosis , Liver Diseases, Alcoholic , Mice, Inbred C57BL , PPAR alpha , Animals , Mice , Humans , Female , Liver Diseases, Alcoholic/pathology , Liver Diseases, Alcoholic/metabolism , Liver Diseases, Alcoholic/prevention & control , Liver Diseases, Alcoholic/etiology , Liver Diseases, Alcoholic/drug therapy , PPAR alpha/metabolism , PPAR alpha/agonists , Chalcones/pharmacology , Liver Cirrhosis/pathology , Liver Cirrhosis/chemically induced , Liver Cirrhosis/metabolism , Liver Cirrhosis/drug therapy , Liver Cirrhosis/prevention & control , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Intestinal Mucosa/metabolism , Caco-2 Cells , Liver/pathology , Liver/drug effects , Liver/metabolism , Ethanol/toxicity , Apoptosis/drug effects , Lipid Metabolism/drug effects , PPAR delta/agonists , PPAR delta/metabolism , Signal Transduction/drug effects , Oxidative Stress/drug effects , PropionatesABSTRACT
Liver cancer is the 4th most lethal form of cancer with a poor prognosis for patients worldwide. Dysregulation of lipid metabolism is related to FA oxidation alternation which can be modified by peroxisome proliferator-activated receptor-α (PPARα). Therefore, it is important to identify the lipid metabolism-related genes regulated by PPARα in liver cancer. Hub genes related to the lipid metabolism pathway of HCC samples treated with PPARα agonist (WY-14,643) were identified through a weighted gene co-expression network analysis (WGCNA). Gene expression and clinical information were obtained from the Gene Expression Omnibus (GEO) database. The network of top main hub genes was visualized by the Cytoscape software using MCODE and CytoHubba plugins. Finally, the expression and clinical association of each hub gene were evaluated using enrichment analysis, TCGA data, GEPIA, GSCA, and q-PCR. Based on our results, the top 5 co-expressed genes including (CPT2, ACSL1, ACSL3, ACOX1, and SLC27A2) were selected as the main hub genes participating in fatty acid metabolism, fatty acid beta-oxidation, and PPAR signaling pathway. All association of higher ACSL3 expression with lower outcomes and survival rates was detected in HCC patients. Therefore, lipid metabolism-related Hub genes regulated by PPARα are potential biomarkers, and they may offer a therapeutical foundation for targeted therapy directed against the HCC antitumor strategy.
Subject(s)
Carcinoma, Hepatocellular , Gene Expression Regulation, Neoplastic , Gene Regulatory Networks , Lipid Metabolism , Liver Neoplasms , PPAR alpha , Humans , PPAR alpha/agonists , PPAR alpha/genetics , PPAR alpha/metabolism , Lipid Metabolism/genetics , Lipid Metabolism/drug effects , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Liver Neoplasms/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/metabolism , Gene Expression Regulation, Neoplastic/drug effects , Coenzyme A Ligases/genetics , Coenzyme A Ligases/metabolism , Gene Expression Profiling/methods , Prognosis , Computational Biology/methodsABSTRACT
Elevated triglyceride levels are associated with an increased risk of cardiovascular events despite guideline-based statin treatment of low-density lipoprotein cholesterol. Peroxisome proliferator-activated receptor α (PPARα) agonists exert a significant triglyceride-lowering effect. However, combination therapy of PPARα agonists with statins poses an increased risk of rhabdomyolysis, which is rare but a major concern of the combination therapy. Pharmacokinetic interaction is suspected to be a contributing factor to the risk. To examine the potential for combination therapy with the selective PPARα modulator (SPPARMα) pemafibrate and statins, drug-drug interaction studies were conducted with open-label, randomized, 6-sequence, 3-period crossover designs for the combination of pemafibrate 0.2 mg twice daily and each of 6 statins once daily: pitavastatin 4 mg/day (n = 18), atorvastatin 20 mg/day (n = 18), rosuvastatin 20 mg/day (n = 29), pravastatin 20 mg/day (n = 18), simvastatin 20 mg/day (n = 20), and fluvastatin 60 mg/day (n = 19), involving healthy male volunteers. The pharmacokinetic parameters of pemafibrate and each of the statins were similar regardless of coadministration. There was neither an effect on the systemic exposure of pemafibrate nor a clinically important increase in the systemic exposure of any of the statins on the coadministration although the systemic exposure of simvastatin was reduced by about 15% and its open acid form by about 60%. The HMG-CoA reductase inhibitory activity in plasma samples from the simvastatin and pemafibrate combination group was about 70% of that in the simvastatin alone group. In conclusion, pemafibrate did not increase the systemic exposure of statins, and vice versa, in healthy male volunteers.
Subject(s)
Benzoxazoles , Butyrates , Cross-Over Studies , Drug Interactions , Healthy Volunteers , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Humans , Male , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/administration & dosage , Adult , Butyrates/pharmacokinetics , Butyrates/administration & dosage , Benzoxazoles/pharmacokinetics , Benzoxazoles/administration & dosage , Benzoxazoles/adverse effects , Benzoxazoles/pharmacology , Young Adult , Middle Aged , PPAR alpha/agonists , PPAR alpha/metabolismABSTRACT
New analogs of the PPAR pan agonist AL29-26 encompassed ligand (S)-7 showing potent activation of PPARα and -γ subtypes as a partial agonist. In vitro experiments and docking studies in the presence of PPAR antagonists were performed to help interpretation of biological data and investigate the main interactions at the binding sites. Further in vitro experiments showed that (S)-7 induced anti-steatotic effects and enhancement of the glucose uptake. This latter effect could be partially ascribed to a significant inhibition of the mitochondrial pyruvate carrier demonstrating that (S)-7 also acted through insulin-independent mechanisms. In vivo experiments showed that this compound reduced blood glucose and lipid levels in a diabetic mice model displaying no toxicity on bone, kidney, and liver. To our knowledge, this is the first example of dual PPARα/γ partial agonist showing these combined effects representing, therefore, the potential lead of new drugs for treatment of dyslipidemic type 2 diabetes.
Subject(s)
Hypoglycemic Agents , PPAR alpha , PPAR gamma , Animals , PPAR alpha/agonists , PPAR alpha/metabolism , PPAR gamma/agonists , PPAR gamma/metabolism , Mice , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/chemical synthesis , Humans , Structure-Activity Relationship , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Male , Molecular Structure , Dose-Response Relationship, Drug , Monocarboxylic Acid Transporters/antagonists & inhibitors , Monocarboxylic Acid Transporters/metabolism , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Molecular Docking Simulation , Mitochondria/drug effects , Mitochondria/metabolismABSTRACT
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.
Subject(s)
Cell Differentiation , Fenofibrate , Myocytes, Cardiac , PPAR alpha , Pluripotent Stem Cells , Humans , Fenofibrate/pharmacology , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/cytology , PPAR alpha/agonists , PPAR alpha/metabolism , Cell Differentiation/drug effects , Pluripotent Stem Cells/drug effects , Pluripotent Stem Cells/metabolism , Pluripotent Stem Cells/cytologyABSTRACT
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 ß-III tubulin expression. Topical fenofibrate reduced neuroinflammation by significantly increasing the levels of nerve growth factor and substance P. It also significantly increased ß-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.
Subject(s)
Cornea , Diabetes Mellitus, Experimental , Diabetic Neuropathies , Fenofibrate , PPAR alpha , Animals , PPAR alpha/agonists , PPAR alpha/metabolism , Mice , Fenofibrate/pharmacology , Fenofibrate/administration & dosage , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/metabolism , Diabetic Neuropathies/drug therapy , Diabetic Neuropathies/metabolism , Cornea/metabolism , Cornea/drug effects , Cornea/innervation , Cornea/pathology , Male , Administration, Oral , Administration, Topical , Corneal Diseases/drug therapy , Corneal Diseases/etiology , Corneal Diseases/metabolism , Corneal Diseases/pathology , Mice, Inbred C57BL , Proteomics/methodsABSTRACT
BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD), and more specifically steatohepatitis may be associated with fat infiltration of skeletal muscles which is known as myosteatosis. Pan-peroxisome proliferator-activated receptor (PPAR) agonists have been shown to promote metabolic dysfunction-associated steatohepatitis (MASH) remission. However, the effect of PPAR agonists on myosteatosis remains to be determined. The aim of this review is to evaluate the effect that PPAR agonists alone or in combination, have on myosteatosis in the context of MASLD. METHODS: Original research reports concerning the impact of PPAR agonists on muscle fat in MASLD were screened from PUBMED and EMBASE databases following the PRISMA methodology. RESULTS: Eleven original manuscripts were included in this review. Two preclinical studies assessed the impact of the PPARα agonist on fat content in the quadriceps muscle and the liver by extracting triglycerides in rats fed a high-fat diet and in insulin-resistant mice. Both models showed muscle and liver triglyceride content reduction using WY14643. Fenofibrate had no significant impact on soleus intramyocellular lipids or liver fat content in insulin-resistant subjects based on proton magnetic resonance spectroscopy. Treatment with PPARδ agonists increased the expression of genes involved in fatty acid oxidation in two studies on muscle cell culture. PPARγ agonists were investigated in two preclinical studies and one clinical study using spectroscopy and computed tomography respectively. In the first preclinical study in Zucker diabetic fatty rats, rosiglitazone reduced muscle lipids and hepatic steatosis. In a second preclinical study using the same animal model, pioglitazone reduced tibialis anterior intramyocellular lipids. In contrast, computed tomography analyses in patients with type 2 diabetes revealed a surface area increase of low-density muscles (suggesting an increase in muscle fat content) after a one-year treatment with rosiglitazone. Varying combinations of PPAR agonists (cevoglitazar, fenofibrate/pioglitazone and muraglitazar) were evaluated in two preclinical studies and one clinical study. In rats, these treatments showed variable results for muscle and liver depending on the combinations studied. In type 2 diabetic patients, treatment with muraglitazar (a PPARα/γ agonist) reduced the intramyocellular lipid content of tibialis anterior as well as liver fat content following spectroscopy assessment. CONCLUSION: The combination of different PPAR agonists could have a positive impact on reducing myosteatosis, in addition to their effect on the liver. Some discrepancies could be explained by the different techniques used to assess muscle lipid content, the muscles assessed and the possible adipogenic effect of PPARγ agonists. Further clinical research is needed to fully assess the efficacy of these treatments on both MASLD progression and associated myosteatosis.
Subject(s)
Fatty Liver , Animals , Humans , Fatty Liver/drug therapy , Fatty Liver/metabolism , Fatty Liver/pathology , Peroxisome Proliferator-Activated Receptors/agonists , Peroxisome Proliferator-Activated Receptors/metabolism , Muscle, Skeletal/drug effects , Muscle, Skeletal/metabolism , Muscle, Skeletal/pathology , Rats , Mice , PPAR alpha/agonists , PPAR alpha/metabolismABSTRACT
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.
Subject(s)
Cell Proliferation , Hepatocytes , Hepatomegaly , Liver , PPAR alpha , Pregnane X Receptor , Pyrimidines , YAP-Signaling Proteins , Animals , Male , Mice , Adaptor Proteins, Signal Transducing/metabolism , Aryl Hydrocarbon Hydroxylases , beta Catenin/metabolism , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Cell Proliferation/drug effects , Cytochrome P-450 CYP3A , Cytochrome P-450 CYP4A/metabolism , Cytochrome P-450 CYP4A/genetics , Cytochrome P450 Family 2 , Cytochrome P450 Family 4/genetics , Cytochrome P450 Family 4/metabolism , Hepatocytes/drug effects , Hepatocytes/metabolism , Hepatocytes/pathology , Hepatomegaly/chemically induced , Hepatomegaly/metabolism , Hepatomegaly/pathology , Ki-67 Antigen/metabolism , Liver/drug effects , Liver/metabolism , Liver/pathology , Membrane Proteins , Mice, Inbred C57BL , Phosphoproteins/metabolism , Phosphoproteins/genetics , PPAR alpha/agonists , PPAR alpha/metabolism , Pregnane X Receptor/metabolism , Pregnane X Receptor/genetics , Pyrimidines/pharmacology , Signal Transduction/drug effects , Steroid Hydroxylases , YAP-Signaling Proteins/metabolismABSTRACT
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.
Subject(s)
Constitutive Androstane Receptor , Hepatocyte Nuclear Factor 4 , Liver , Mice, Knockout , PPAR alpha , Pregnane X Receptor , Receptors, Cytoplasmic and Nuclear , Animals , Hepatocyte Nuclear Factor 4/metabolism , Hepatocyte Nuclear Factor 4/genetics , Liver/metabolism , Liver/drug effects , PPAR alpha/agonists , PPAR alpha/metabolism , PPAR alpha/genetics , Pregnane X Receptor/genetics , Pregnane X Receptor/metabolism , Receptors, Cytoplasmic and Nuclear/genetics , Receptors, Cytoplasmic and Nuclear/agonists , Receptors, Cytoplasmic and Nuclear/metabolism , Mice , Receptors, Steroid/genetics , Receptors, Steroid/metabolism , Receptors, Steroid/agonists , Receptors, Aryl Hydrocarbon/agonists , Receptors, Aryl Hydrocarbon/genetics , Receptors, Aryl Hydrocarbon/metabolism , Mice, Inbred C57BL , Male , Pyrimidines/pharmacology , Polychlorinated Dibenzodioxins/toxicity , Pyridines/pharmacologyABSTRACT
OBJECTIVE: The prevalence of metabolic diseases is increasing globally at an alarming rate; thus, it is essential that effective, accessible, low-cost therapeutics are developed. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that tightly regulate glucose homeostasis and lipid metabolism and are important drug targets for the treatment of type 2 diabetes and dyslipidemia. We previously identified LDT409, a fatty acid-like compound derived from cashew nut shell liquid, as a novel pan-active PPARα/γ/δ compound. Herein, we aimed to assess the efficacy of LDT409 in vivo and investigate the molecular mechanisms governing the actions of the fatty acid mimetic LDT409 in diet-induced obese mice. METHODS: C57Bl/6 mice (6-11-month-old) were fed a chow or high fat diet (HFD) for 4 weeks; mice thereafter received once daily intraperitoneal injections of vehicle, 10 mg/kg Rosiglitazone, 40 mg/kg WY14643, or 40 mg/kg LDT409 for 18 days while continuing the HFD. During treatments, body weight, food intake, glucose and insulin tolerance, energy expenditure, and intestinal lipid absorption were measured. On day 18 of treatment, tissues and plasma were collected for histological, molecular, and biochemical analysis. RESULTS: We found that treatment with LDT409 was effective at reversing HFD-induced obesity and associated metabolic abnormalities in mice. LDT409 lowered food intake and hyperlipidemia, while improving insulin tolerance. Despite being a substrate of both PPARα and PPARγ, LDT409 was crucial for promoting hepatic fatty acid oxidation and reducing hepatic steatosis in HFD-fed mice. We also highlighted a role for LDT409 in white and brown adipocytes in vitro and in vivo where it decreased fat accumulation, increased lipolysis, induced browning of WAT, and upregulated thermogenic gene Ucp1. Remarkably, LDT409 reversed HFD-induced weight gain back to chow-fed control levels. We determined that the LDT409-induced weight-loss was associated with a combination of increased energy expenditure (detectable before weight loss was apparent), decreased food intake, increased systemic fat utilization, and increased fecal lipid excretion in HFD-fed mice. CONCLUSIONS: Collectively, LDT409 represents a fatty acid mimetic that generates a uniquely favorable metabolic response for the treatment of multiple abnormalities including obesity, dyslipidemia, metabolic dysfunction-associated steatotic liver disease, and diabetes. LDT409 is derived from a highly abundant natural product-based starting material and its development could be pursued as a therapeutic solution to the global metabolic health crisis.
Subject(s)
Diet, High-Fat , Fatty Acids , Mice, Inbred C57BL , Obesity , Animals , Mice , Obesity/metabolism , Obesity/drug therapy , Diet, High-Fat/adverse effects , Male , Fatty Acids/metabolism , Fatty Liver/metabolism , Fatty Liver/drug therapy , PPAR alpha/metabolism , PPAR alpha/agonists , Lipid Metabolism/drug effects , Peroxisome Proliferator-Activated Receptors/metabolism , Peroxisome Proliferator-Activated Receptors/agonists , Liver/metabolism , Liver/drug effects , Non-alcoholic Fatty Liver Disease/metabolism , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/etiologyABSTRACT
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, PPARß/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.
Subject(s)
Diabetes Mellitus, Type 2 , Peroxisome Proliferator-Activated Receptors , Humans , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/metabolism , Peroxisome Proliferator-Activated Receptors/agonists , Peroxisome Proliferator-Activated Receptors/metabolism , Fatty Liver/drug therapy , Insulin Resistance/physiology , PPAR alpha/agonists , PPAR alpha/metabolism , PPAR gamma/agonists , PPAR gamma/metabolism , AnimalsABSTRACT
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.
Subject(s)
Hepatocytes , PPAR alpha , PPAR gamma , Transcriptome , Animals , Hepatocytes/drug effects , Hepatocytes/metabolism , PPAR alpha/agonists , PPAR alpha/genetics , PPAR alpha/metabolism , Humans , PPAR gamma/genetics , PPAR gamma/agonists , PPAR gamma/metabolism , Transcriptome/drug effects , Male , Mice , Fluorocarbons/toxicity , Rats , Propionates/toxicity , Cells, Cultured , Gene Expression Profiling , Rosiglitazone/pharmacology , Rosiglitazone/toxicity , Rats, Sprague-Dawley , Mice, Inbred C57BL , Species Specificity , Dose-Response Relationship, Drug , Butyrates , Phenylurea CompoundsABSTRACT
Recent in vitro transcriptomic analyses for the short-chain polyfluoroalkyl substance, HFPO-DA (ammonium, 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate), support conclusions from in vivo data that HFPO-DA-mediated liver effects in mice are part of the early key events of the peroxisome proliferator-activated receptor alpha (PPARα) activator-induced rodent hepatocarcinogenesis mode of action (MOA). Transcriptomic responses in HFPO-DA-treated rodent hepatocytes have high concordance with those treated with a PPARα agonist and lack concordance with those treated with PPARγ agonists or cytotoxic agents. To elucidate whether HFPO-DA-mediated transcriptomic responses in mouse liver are PPARα-dependent, additional transcriptomic analyses were conducted on samples from primary PPARα knockout (KO) and wild-type (WT) mouse hepatocytes exposed for 12, 24, or 72 h with various concentrations of HFPO-DA, or well-established agonists of PPARα (GW7647) and PPARγ (rosiglitazone), or cytotoxic agents (acetaminophen or d-galactosamine). Pathway and predicted upstream regulator-level responses were highly concordant between HFPO-DA and GW7647 in WT hepatocytes. A similar pattern was observed in PPARα KO hepatocytes, albeit with a distinct temporal and concentration-dependent delay potentially mediated by compensatory responses. This delay was not observed in PPARα KO hepatocytes exposed to rosiglitazone, acetaminophen, d-galactosamine. The similarity in transcriptomic signaling between HFPO-DA and GW7647 in both the presence and absence of PPARα in vitro indicates these compounds share a common MOA.
Subject(s)
Hepatocytes , Mice, Knockout , PPAR alpha , PPAR gamma , Transcriptome , Animals , Hepatocytes/drug effects , Hepatocytes/metabolism , PPAR alpha/agonists , PPAR alpha/genetics , PPAR alpha/metabolism , PPAR gamma/agonists , PPAR gamma/genetics , PPAR gamma/metabolism , Transcriptome/drug effects , Mice , Fluorocarbons/toxicity , Propionates/pharmacology , Propionates/toxicity , Mice, Inbred C57BL , Male , Cells, Cultured , Gene Expression Profiling , Acetaminophen/toxicity , Cytotoxins/toxicity , Butyrates , Phenylurea CompoundsABSTRACT
Saroglitazar (SARO), a dual peroxisome proliferator activated receptor (PPAR)-α/γ agonist, has been used to treat metabolic diseases such as insulin resistance and diabetic dyslipidemia in patients with non-alcoholic fatty liver disease (NAFLD). SARO, administered at a dose of 4 mg/day, has been consistently studied in clinical trials with different time points ranging from 4 to 24 weeks with NAFLD patients. Due to its PPAR-γ agonistic action, SARO prevents adipose tissue-mediated fatty acid delivery to the liver by increasing insulin sensitivity and regulating adiponectin and leptin levels in adipose tissue. In hepatocytes, SARO induces fatty acid ß-oxidation in mitochondria and transcriptionally activates lipid metabolizing genes in peroxisomes. SARO inhibits insulin resistance, thereby preventing the activation of sterol regulatory element-binding proteins -1c and carbohydrate response element binding protein in hepatocytes through its PPAR-α agonistic action. SARO treatment reduces lipotoxicity-mediated oxidative stress by activating the nuclear factor erythroid 2-related factor 2 and transcriptionally expressing the antioxidants from the antioxidant response element in the nucleus through its PPAR-γ agonistic action. SARO provides a PPAR-α/γ-mediated anti-inflammatory effect by preventing the phosphorylation of mitogen-activated protein kinases (JNK and ERK) and nuclear factor kappa B in hepatocytes. Additionally, SARO interferes with transforming growth factor-ß/Smad downstream signaling, thereby reducing liver fibrosis progression through its PPAR-α/γ agonistic actions. Thus, SARO improves insulin resistance and dyslipidemia in NAFLD, reduces lipid accumulation in the liver, and thereby prevents mitochondrial toxicity, oxidative stress, inflammation, and fibrosis progression. This review summarizes the possible molecular mechanism of SARO in the NAFLD.
Subject(s)
Non-alcoholic Fatty Liver Disease , PPAR alpha , PPAR gamma , Humans , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/metabolism , PPAR alpha/agonists , PPAR alpha/metabolism , PPAR gamma/agonists , PPAR gamma/metabolism , Animals , Phenylpropionates/therapeutic use , Phenylpropionates/pharmacology , Insulin Resistance , PyrrolesABSTRACT
OBJECTIVE: Previous studies have revealed that Propane-2-sulfonic acid octadec-9-enyl-amide(N15) exerts a protective role in the inflammatory response after ischemic stroke and in neuronal damage. However, little is known about N15 in Alzheimer's disease (AD). The aim of this study was to investigate the effects of N15 on AD and explore the underlying molecular mechanism. METHODS: AD mice model was established by lateral ventricular injection with Aß25-35. N15 was daily intraperitoneal administered for 28 days. Morris Water Maze was used to evaluate the neurocognitive function of the mice. The expression of PPARα/γ, brain-derived neurotrophic factor (BDNF), Neurotrophin-3 (NT3), ADAM10, PS1 and BACE1 were measured by qPCR. Aß amyloid in the hippocampus was measured by Congo red assay. Toluidine blue staining was used to detect the neuronal apoptosis. Protein levels of ADAM10, PS1 and BACE1 were determined using immunoblotting. RESULTS: N15 treatment significantly reduced neurocognitive dysfunction, which also significantly activated the expression of PPARα/γ at an optimal dose of 200 mg/kg. Administration of N15 alleviated the formation of Aß amyloid in the hippocampus of AD mice, enhanced the BDNF mRNA expression, decreased the mRNA and protein levels of PS1 and BACE1, upregulated ADAM10 mRNA and protein levels. CONCLUSION: N15 exerts its neuroprotective effects through the activation of PPARα/γ and may be a potential drug for the treatment of AD.
Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , PPAR alpha , Sulfonic Acids , Animals , Male , Mice , Alzheimer Disease/drug therapy , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/drug effects , Amyloid beta-Peptides/metabolism , Amyloid Precursor Protein Secretases/metabolism , Brain-Derived Neurotrophic Factor/metabolism , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/pathology , Maze Learning/drug effects , Memory/drug effects , Mice, Inbred C57BL , Neuroprotective Agents/pharmacology , Peptide Fragments , PPAR alpha/agonists , PPAR alpha/metabolism , PPAR gamma/agonists , PPAR gamma/metabolism , Sulfonic Acids/pharmacology , PPAR-gamma Agonists/pharmacologySubject(s)
PPAR alpha , PPAR delta , PPAR alpha/agonists , Humans , PPAR delta/genetics , Animals , Mice , Fatty LiverABSTRACT
This study examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α agonist, on the serum biochemical parameters of male patients with coronary artery disease and metabolic syndrome (MetS). This was a post hoc analysis of a randomized, crossover study that treated hypertriglyceridemia with pemafibrate or bezafibrate for 24 weeks, followed by a crossover of another 24 weeks. Of the 60 patients enrolled in the study, 55 were male. Forty-one of 55 male patients were found to have MetS. In this sub-analysis, male patients with MetS (MetS group, n = 41) and those without MetS (non-MetS group, n = 14) were compared. The primary endpoint was a change in fasting serum triglyceride (TG) levels during pemafibrate therapy, and the secondary endpoints were changes in insulin resistance-related markers and liver function parameters. Serum TG levels significantly decreased (MetS group, from 266.6 to 148.0 mg/dL, p < 0.001; non-MetS group, from 203.9 to 97.6 mg/dL, p < 0.001); however, a percent change (%Change) was not significantly different between the groups (- 44.1% vs. - 51.6%, p = 0.084). Serum insulin levels and homeostasis model assessment of insulin resistance significantly decreased in the MetS group but not in the non-MetS group. %Change in liver enzyme levels was markedly decreased in the MetS group compared with that in the non-MetS group (alanine aminotransferase, - 25.1% vs. - 11.3%, p = 0.027; gamma-glutamyl transferase, - 45.8% vs. - 36.2%, p = 0.020). In conclusion, pemafibrate can effectively decrease TG levels in patients with MetS, and it may be a more efficient drug for improving insulin resistance and liver function in such patients.
Subject(s)
Benzoxazoles , Butyrates , Coronary Artery Disease , Cross-Over Studies , Hypertriglyceridemia , Insulin Resistance , Metabolic Syndrome , Humans , Male , Metabolic Syndrome/blood , Metabolic Syndrome/drug therapy , Metabolic Syndrome/complications , Metabolic Syndrome/diagnosis , Hypertriglyceridemia/blood , Hypertriglyceridemia/drug therapy , Hypertriglyceridemia/complications , Hypertriglyceridemia/diagnosis , Middle Aged , Coronary Artery Disease/blood , Coronary Artery Disease/drug therapy , Benzoxazoles/therapeutic use , Benzoxazoles/pharmacology , Butyrates/therapeutic use , Butyrates/pharmacology , Treatment Outcome , Aged , Triglycerides/blood , Hypolipidemic Agents/therapeutic use , Hypolipidemic Agents/pharmacology , Biomarkers/blood , PPAR alpha/agonists , Bezafibrate/therapeutic use , Bezafibrate/pharmacologyABSTRACT
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.
Subject(s)
Head and Neck Neoplasms , Oleic Acid , PPAR alpha , Animals , PPAR alpha/agonists , Mice , Oleic Acid/pharmacology , Humans , Head and Neck Neoplasms/immunology , Fenofibrate/pharmacology , Cell Line, Tumor , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/drug effects , Fatty Acids/metabolism , Disease Models, AnimalABSTRACT
Pulmonary fibrosis (PF) is a complex disorder with high morbidity and mortality. Limited efficacies of the available drugs drive researchers to seek for new therapies. Saroglitazar (Saro), a full (PPAR α/γ) agonist, is devoid of known PPAR-mediated adverse effects. Breast milk mesenchymal stem cells (BrMSCs) are contemplated to be the ideal cell type harboring differentiation/anti-inflammatory/immunosuppressive properties. Accordingly, our aims were to investigate the potential roles of Saro and/or BrMSCs in PF and to spot their underlying protective mechanisms. In this study, PF was induced by bleomycin (BLM) via intratracheal instillation. Treatment started 14 days later. Animals were treated with oral saroglitazar (3 mg/kg daily) or intraperitoneal single BrMSCs injection (0.5 ml phosphate buffer saline (PBS) containing 2 × 107 cells) or their combination with same previous doses. At the work end, 24 h following the 6 weeks of treatment period, the levels of oxidative (MDA, SOD), inflammatory (IL-1ß, IL-10), and profibrotic markers (TGF-ß, αSMA) were assessed. The autophagy-related genes (LC3, Beclin) and the expression of PPAR-α/γ and SMAD-3/7 were evaluated. Furthermore, immunohistochemical and histological work were evaluated. Our study revealed marked lung injury influenced by BLM with severe oxidative/inflammatory/fibrotic damage, autophagy inhibition, and deteriorated lung histology. Saro and BrMSCs repaired the lung structure worsened by BLM. Treatments greatly declined the oxidative/inflammatory markers. The pro-fibrotic TGF-ß, αSMA, and SMAD-3 were decreased. Contrarily, autophagy markers were increased. SMAD-7 and PPAR α/γ were activated denoting their pivotal antifibrotic roles. Co-administration of Saro and BrMSCs revealed the top results. Our findings support the study hypothesis that Saro and BrMSCs can be proposed as potential treatments for IPF.
Subject(s)
Bleomycin , Mesenchymal Stem Cells , Phenylpropionates , Pulmonary Fibrosis , Transforming Growth Factor beta , Animals , Pulmonary Fibrosis/metabolism , Pulmonary Fibrosis/pathology , Pulmonary Fibrosis/drug therapy , Transforming Growth Factor beta/metabolism , Mesenchymal Stem Cells/drug effects , Mesenchymal Stem Cells/metabolism , Phenylpropionates/pharmacology , Female , Signal Transduction/drug effects , PPAR gamma/agonists , PPAR gamma/metabolism , Male , Mesenchymal Stem Cell Transplantation/methods , Lung/drug effects , Lung/pathology , Lung/metabolism , PPAR alpha/agonists , PPAR alpha/metabolism , PyrrolesABSTRACT
Peroxisome proliferator-activated receptors (PPARs) play a major role in regulating inflammatory processes, and dual or pan-PPAR agonists with PPARγ partial activation have been recognised to be useful to manage both metabolic syndrome and metabolic dysfunction-associated fatty liver disease (MAFLD). Previous works have demonstrated the capacity of 2-prenylated benzopyrans as PPAR ligands. Herein, we have replaced the isoprenoid bond by hydrazone, a highly attractive functional group in medicinal chemistry. In an attempt to discover novel and safety PPAR activators, we efficiently prepared benzopyran hydrazone/hydrazine derivatives containing benzothiazole (series 1) or 5-chloro-3-(trifluoromethyl)-2-pyridine moiety (series 2) with a 3- or 7-carbon side chain at the 2-position of the benzopyran nucleus. Benzopyran hydrazones 4 and 5 showed dual hPPARα/γ agonism, while hydrazone 14 exerted dual hPPARα/δ agonism. These three hydrazones greatly attenuated inflammatory markers such as IL-6 and MCP-1 on the THP-1 macrophages via NF-κB activation. Therefore, we have discovered novel hits (4, 5 and 14), containing a hydrazone framework with dual PPARα/γ or PPARα/δ partial agonism, depending on the length of the side chain. Benzopyran hydrazones emerge as potential lead compounds which could be useful for treating metabolic diseases.