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International Journal of Molecular... Sep 2021Peroxisome proliferator-activated receptors (PPARs) are ligand-modulated nuclear receptors that play pivotal roles in nutrient sensing, metabolism, and lipid-related... (Review)
Review
Peroxisome proliferator-activated receptors (PPARs) are ligand-modulated nuclear receptors that play pivotal roles in nutrient sensing, metabolism, and lipid-related processes. Correct control of their target genes requires tight regulation of the expression of different PPAR isoforms in each tissue, and the dysregulation of PPAR-dependent transcriptional programs is linked to disorders, such as metabolic and immune diseases or cancer. Several PPAR regulators and PPAR-regulated factors are epigenetic effectors, including non-coding RNAs, epigenetic enzymes, histone modifiers, and DNA methyltransferases. In this review, we examine advances in PPARα and PPARγ-related epigenetic regulation in metabolic disorders, including obesity and diabetes, immune disorders, such as sclerosis and lupus, and a variety of cancers, providing new insights into the possible therapeutic exploitation of PPAR epigenetic modulation.
Topics: Animals; DNA Methylation; Epigenesis, Genetic; Gene Expression Regulation; Humans; Immune System Diseases; Metabolic Diseases; Neoplasms; PPAR alpha; PPAR gamma
PubMed: 34638914
DOI: 10.3390/ijms221910573 -
Biochemical Pharmacology Mar 2023Inherited metabolic disorders (IMDs) are genetic disorders that cause a disruption of a specific metabolic pathway leading to biochemical, clinical and... (Review)
Review
Inherited metabolic disorders (IMDs) are genetic disorders that cause a disruption of a specific metabolic pathway leading to biochemical, clinical and pathophysiological sequelae. While the metabolite abnormalities in body fluids and tissues can usually be defined by directed or broad-spectrum metabolomic analysis, the pathophysiology of these changes is often not obvious. Mounting evidence has revealed that secondary mitochondrial dysfunction, mainly oxidative phosphorylation impairment and elevated reactive oxygen species, plays a pivotal role in many disorders. Peroxisomal proliferator-activated receptors (PPARs) consist of a group of nuclear hormone receptors (PPARα, PPARβ/δ, and PPARγ) that regulate multiple cellular functions and processes, including response to oxidative stress, inflammation, lipid metabolism, and mitochondrial bioenergetics and biogenesis. In this context, the activation of PPARs has been shown to stimulate oxidative phosphorylation and reduce reactive species levels. Thus, pharmacological treatment with PPAR activators, such as fibrates, has gained much attention in the last 15 years. This review summarizes preclinical (animal models and patient-derived cells) and clinical data on the effect of PPARs in IMDs.
Topics: Animals; PPAR alpha; PPAR gamma; PPAR delta; Metabolic Diseases; Lipid Metabolism
PubMed: 36709926
DOI: 10.1016/j.bcp.2023.115433 -
Diabetes Jul 2023Monocyte activation plays an important role in diabetic complications such as diabetic retinopathy (DR). However, the regulation of monocyte activation in diabetes...
Monocyte activation plays an important role in diabetic complications such as diabetic retinopathy (DR). However, the regulation of monocyte activation in diabetes remains elusive. Fenofibrate, an agonist of peroxisome proliferator-activated receptor-α (PPARα), has shown robust therapeutic effects on DR in patients with type 2 diabetes. Here we found that PPARα levels were significantly downregulated in monocytes from patients with diabetes and animal models, correlating with monocyte activation. Fenofibrate attenuated monocyte activation in diabetes, while PPARα knockout alone induced monocyte activation. Furthermore, monocyte-specific PPARα overexpression ameliorated, while monocyte-specific PPARα knockout aggravated monocyte activation in diabetes. PPARα knockout impaired mitochondrial function while also increasing glycolysis in monocytes. PPARα knockout increased cytosolic mitochondrial DNA release and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in monocytes under diabetic conditions. STING knockout or STING inhibitor attenuated monocyte activation induced by diabetes or by PPARα knockout. These observations suggest that PPARα negatively regulates monocyte activation through metabolic reprogramming and interaction with the cGAS-STING pathway.
Topics: Animals; PPAR alpha; Fenofibrate; Monocytes; Diabetes Mellitus, Type 2; Diabetic Retinopathy; Nucleotidyltransferases
PubMed: 37058417
DOI: 10.2337/db22-0654 -
Nutrients Dec 2021Bariatric surger (BS) is characterized by lipid metabolic changes as a response to the massive release of non-esterified fatty acids (NEFA) from adipose depots. The...
Bariatric surger (BS) is characterized by lipid metabolic changes as a response to the massive release of non-esterified fatty acids (NEFA) from adipose depots. The study aimed at evaluating changes in polyunsaturated fatty acids (PUFA) metabolism and biosynthesis of the lipid mediators -acylethanolamines (NAE), as indices of nuclear peroxisome proliferator-activated receptor (PPAR)-α activation. The observational study was performed on 35 subjects (27 female, 8 male) with obesity, undergoing bariatric surgery. We assessed plasma FA and NAE profiles by LC-MS/MS, clinical parameters and anthropometric measures before and 1 and 6 months after bariatric surgery. One month after bariatric surgery, as body weight and clinical parameters improved significantly, we found higher plasma levels of -oleoylethanolamine, arachidonic and a 22:6-n3/20:5-n3 ratio as evidence of PPAR-α activation. These changes corresponded to higher circulating levels of NEFA and a steep reduction of the fat mass. After 6 months 22:6-n3/20:5-n3 remained elevated and fat mass was further reduced. Our data suggest that the massive release of NEFA from adipose tissue at 1-Post, possibly by inducing PPAR-α, may enhance FA metabolism contributing to fat depot reduction and improved metabolic parameters in the early stage. However, PUFA metabolic changes favor n6 PUFA biosynthesis, requiring a nutritional strategy aimed at reducing the n6/n3 PUFA ratio.
Topics: Adipose Tissue; Adult; Arachidonic Acid; Bariatric Surgery; Body Composition; Endocannabinoids; Ethanolamines; Fatty Acids, Unsaturated; Female; Humans; Male; Obesity; Oleic Acids; PPAR alpha; Postoperative Period
PubMed: 34959892
DOI: 10.3390/nu13124340 -
Hepatology (Baltimore, Md.) Nov 2023Liver fibrosis is the result of sustained chronic liver injury and inflammation leading to hepatocyte cell death followed by the formation of fibrous scars, which is the...
Liver fibrosis is the result of sustained chronic liver injury and inflammation leading to hepatocyte cell death followed by the formation of fibrous scars, which is the hallmark of NASH and alcoholic steatohepatitis and can lead to cirrhosis, HCC, and liver failure. Although progress has been made in understanding the pathogenesis and clinical consequences of hepatic fibrosis, therapeutic strategies for this disease are limited. Preclinical studies suggest that peroxisome proliferator-activated receptor alpha plays an important role in preventing the development of liver fibrosis by activating genes involved in detoxifying lipotoxicity and toxins, transrepressing genes involved in inflammation, and inhibiting activation of hepatic stellate cells. Given the robust preclinical data, several peroxisome proliferator-activated receptor alpha agonists have been tested in clinical trials for liver fibrosis. Here, we provide an update on recent progress in understanding the mechanisms by which peroxisome proliferator-activated receptor alpha prevents fibrosis and discuss the potential of targeting PPARα for the development of antifibrotic treatments.
Topics: Humans; Carcinoma, Hepatocellular; Fibrosis; Inflammation; Liver; Liver Cirrhosis; Liver Neoplasms; Non-alcoholic Fatty Liver Disease; PPAR alpha
PubMed: 36626642
DOI: 10.1097/HEP.0000000000000182 -
Cardiovascular Toxicology Apr 2022Cardiotoxicity can be a complication of both drugs and a variety of other chemicals that affects morbidity, quality of life, and even mortality. The accumulation of... (Review)
Review
Cardiotoxicity can be a complication of both drugs and a variety of other chemicals that affects morbidity, quality of life, and even mortality. The accumulation of lipids and inflammation have been implicated in the development of cardiotoxicity. The peroxisome proliferator-activated receptors (PPARs), a family of transcription factors, have a role in controlling the cardiac expression of genes involved in lipid and glucose metabolism and the inflammatory response. The different PPAR isoforms, PPARα, PPARγ, and PPARβ/δ, have a role in multiple functions in cardiac tissue. The protective nature of several naturally occurring chemicals (NCs) against cardiotoxicity by targeting PPARα and PPARγ has been reported. The literature related to the ability of several NCs to modulate cardiotoxicity through targeting the AMP-activated protein kinase (AMPK)/the PPARγ coactivator-1 alpha (PGC-1α)/PPARα, the PPARα/the nuclear factor-kappa B (NF-κB), and the PPARγ/the nuclear factor-erythroid 2 related factors 2 (Nrf2)/the heme oxygenase-1 (HO-1)/NF-κB signaling pathways are reviewed.
Topics: Cardiotoxicity; Humans; NF-kappa B; PPAR alpha; PPAR gamma; Quality of Life; Signal Transduction
PubMed: 35067839
DOI: 10.1007/s12012-021-09715-5 -
Biomedicine & Pharmacotherapy =... May 2023Breast cancer has been confirmed to have lipid disorders in the tumour microenvironment. Peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated... (Review)
Review
Breast cancer has been confirmed to have lipid disorders in the tumour microenvironment. Peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcriptional factor that belongs to the family of nuclear receptors. PPARα regulates the expression of genes involved in fatty acid homeostasis and is a major regulator of lipid metabolism. Because of its effects on lipid metabolism, an increasing number of studies have investigated the relationship of PPARα with breast cancer. PPARα has been shown to impact the cell cycle and apoptosis in normal cells and tumoral cells through regulating genes of the lipogenic pathway, fatty acid oxidation, fatty acid activation, and uptake of exogenous fatty acids. Besides, PPARα is involved in the regulation of the tumour microenvironment (anti-inflammation and inhibition of angiogenesis) by modulating different signal pathways such as NF-κB and PI3K/AKT/mTOR. Some synthetic PPARα ligands are used in adjuvant therapy for breast cancer. PPARα agonists are reported to reduce the side effects of chemotherapy and endocrine therapy. In addition, PPARα agonists enhance the curative effects of targeted therapy and radiation therapy. Interestingly, with the emerging role of immunotherapy, attention has been focused on the tumour microenvironment. The dual functions of PPARα agonists in immunotherapy need further research. This review aims to consolidate the operations of PPARα in lipid-related and other ways, as well as discuss the current and potential applications of PPARα agonists in tackling breast cancer.
Topics: Humans; Female; PPAR alpha; Breast Neoplasms; Phosphatidylinositol 3-Kinases; Gene Expression Regulation; Lipid Metabolism; Fatty Acids; Tumor Microenvironment
PubMed: 36812713
DOI: 10.1016/j.biopha.2023.114420 -
Chemical Biology & Drug Design Dec 2022PPARs stand for 'peroxisome proliferator-activated receptors' and are ligand-activated transcription factors of nuclear hormone receptor superfamily. A list of the most... (Review)
Review
PPARs stand for 'peroxisome proliferator-activated receptors' and are ligand-activated transcription factors of nuclear hormone receptor superfamily. A list of the most commonly used single receptor PPAR agonists, that is α (alpha) PPAR agonists, β/δ(beta/delta) PPAR agonists, γ(gamma) PPAR agonists, along with pan PPAR agents, that are being researched on, are marketed, are in clinical trials or are being studied for further derivative findings, has been listed. Type 2 diabetes constitutes about 90% of total diabetes cases. Pan PPAR ligands could very well pave the foundation for a new class of agents, that can act on all 3 PPAR receptors, and produce better effects in general, than the individual receptor-acting ligands or dual combination ligands (α/ γ). In this review paper, we have detailed various pan PPAR agonists that can be used to treat type 2 diabetes, which can generate potential derivatives as well.
Topics: Humans; Peroxisome Proliferator-Activated Receptors; Diabetes Mellitus, Type 2; Ligands; Hypoglycemic Agents; Receptors, Cytoplasmic and Nuclear; PPAR gamma; PPAR alpha; PPAR delta
PubMed: 34990085
DOI: 10.1111/cbdd.14020 -
PloS One 2020Peroxisome proliferator-activated receptor α/δ (PPAR α/δ), regulating glucolipid metabolism and immune inflammation, has been identified as an effective therapeutic...
Peroxisome proliferator-activated receptor α/δ (PPAR α/δ), regulating glucolipid metabolism and immune inflammation, has been identified as an effective therapeutic target in non-alcoholic steatohepatitis (NASH). Dual PPAR α/δ agonist, such as GFT505 (also known as elafibranor), demonstrated potential therapeutic effect for NASH in clinical trials. To profile the regulatory network of PPAR α/δ agonist in NASH, the choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) induced NASH model was used to test the pharmacodynamics and transcriptome regulation of GFT505 in this study. The results showed that GFT505 ameliorated hepatic steatosis, inflammation and fibrosis in CDAHFD mice model. RNA-sequencing yielded 3995 up-regulated and 3576 down-regulated genes with GFT505 treatment. And the most significant differentialy expressed genes involved in glucolipid metabolism (Pparα, Acox1, Cpt1b, Fabp4, Ehhadh, Fabp3), inflammation (Ccl6, Ccl9, Cxcl14) and fibrosis (Timp1, Lamc3, Timp2, Col3a1, Col1a2, Col1a1, Hapln4, Timp3, Pik3r5, Pdgfα, Pdgfβ, Tgfβ1, Tgfβ2) were confirmed by RT-qPCR. The down-regulated genes were enriched in cytokine-cytokine receptor interaction pathway and ECM-receptor interaction pathway, while the up-regulated genes were enriched in PPAR signaling pathway and fatty acid degradation pathway. This study provides clues and basis for further understanding on the mechanism of PPAR α/δ agonist on NASH.
Topics: Amino Acids; Animals; Chalcones; Choline; Choline Deficiency; Diet, High-Fat; Disease Models, Animal; Gene Expression Regulation; Humans; Mice; Non-alcoholic Fatty Liver Disease; PPAR alpha; Propionates; Receptors, Cytoplasmic and Nuclear; Signal Transduction
PubMed: 33326461
DOI: 10.1371/journal.pone.0243911 -
The Journal of Endocrinology Oct 2020Fructose dietary intake affects the composition of the intestinal microbiota and influences the development of hepatic steatosis. Endotoxins produced by gram-negative...
Fructose dietary intake affects the composition of the intestinal microbiota and influences the development of hepatic steatosis. Endotoxins produced by gram-negative bacteria alter intestinal permeability and cause bacterial translocation. This study evaluated the effects of gut microbiota modulation by a purified PPAR-alpha agonist (WY14643), a DPP-4 inhibitor (linagliptin), or their association on intestinal barrier integrity, endotoxemia, and hepatic energy metabolism in high-fructose-fed C57BL/6 mice. Fifty mice were divided to receive the control diet (C group) or the high-fructose diet (HFRU) for 12 weeks. Subsequently, the HFRU group was divided to initiate the treatment with PPAR-alpha agonist (3.5 mg/kg/BM) and DPP-4 inhibitor (15 mg/kg/BM). The HFRU group had glucose intolerance, endotoxemia, and dysbiosis (with increased Proteobacteria) without changes in body mass in comparison with the C group. HFRU group showed damaged intestinal ultrastructure, which led to liver inflammation and marked hepatic steatosis in the HFRU group when compared to the C group. PPAR-alpha activation and DPP-4 inhibition countered glucose intolerance, endotoxemia, and dysbiosis, ameliorating the ultrastructure of the intestinal barrier and reducing Tlr4 expression in the liver of treated animals. These beneficial effects suppressed lipogenesis and mitigated hepatic steatosis. In conclusion, the results herein propose a role for PPAR-alpha activation, DPP-4 inhibition, and their association in attenuating hepatic steatosis by gut-liver axis modulation in high-fructose mice model. These observations suggest these treatments as potential targets to treat hepatic steatosis and avoid its progression.
Topics: Animals; Blood Glucose; Diet; Dipeptidyl-Peptidase IV Inhibitors; Endotoxemia; Fatty Liver; Fructose; Gastrointestinal Microbiome; Intestines; Linagliptin; Lipogenesis; Liver; Male; Mice; Mice, Inbred C57BL; PPAR alpha; Peroxisome Proliferators; Pyrimidines
PubMed: 32698143
DOI: 10.1530/JOE-20-0139