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Gastroenterology Sep 2019Many genetic and environmental factors, including family history, dietary fat, and inflammation, increase risk for colon cancer development. Peroxisome...
BACKGROUND & AIMS
Many genetic and environmental factors, including family history, dietary fat, and inflammation, increase risk for colon cancer development. Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that regulates systemic lipid homeostasis. We explored the role of intestinal PPARα in colon carcinogenesis.
METHODS
Colon cancer was induced in mice with intestine-specific disruption of Ppara (Ppara), Ppara (control), and mice with disruption of Ppara that express human PPARA (human PPARA transgenic mice), by administration of azoxymethane with or without dextran sulfate sodium (DSS). Colons were collected from mice and analyzed by immunoblots, quantitative polymerase chain reaction, and histopathology. Liquid chromatography coupled with mass spectrometry-based metabolomic analyses were performed on urine and colons. We used molecular biology and biochemical approaches to study mechanisms in mouse colons, primary intestinal epithelial cells, and colon cancer cell lines. Gene expression data and clinical features of patients with colorectal tumors were obtained from Oncomine, and human colorectal-tumor specimens and adjacent normal tissues were collected and analyzed by immunohistochemistry.
RESULTS
Levels of Ppara messenger RNA were reduced in colon tumors from mice. Ppara mice developed more and larger colon tumors than control mice following administration of azoxymethane, with or without DSS. Metabolomic analyses revealed increases in methylation-related metabolites in urine and colons from Ppara mice, compared with control mice, following administration of azoxymethane, with or without DSS. Levels of DNA methyltransferase 1 (DNMT1) and protein arginine methyltransferase 6 (PRMT6) were increased in colon tumors from Ppara mice, compared with colon tumors from control mice. Depletion of PPARα reduced the expression of retinoblastoma protein, resulting in increased expression of DNMT1 and PRMT6. DNMT1 and PRMT6 decreased expression of the tumor suppressor genes Cdkn1a (P21) and Cdkn1b (p27) via DNA methylation and histone H3R2 dimethylation-mediated repression of transcription, respectively. Fenofibrate protected human PPARA transgenic mice from azoxymethane and DSS-induced colon cancer. Human colon adenocarcinoma specimens had lower levels of PPARA and retinoblastoma protein and higher levels of DNMT1 and PRMT6 than normal colon tissues.
CONCLUSIONS
Loss of PPARα from the intestine promotes colon carcinogenesis by increasing DNMT1-mediated methylation of P21 and PRMT6-mediated methylation of p27 in mice. Human colorectal tumors have lower levels of PPARA messenger RNA and protein than nontumor tissues. Agents that activate PPARα might be developed for chemoprevention or treatment of colon cancer.
Topics: Adenocarcinoma; Animals; Anticarcinogenic Agents; Case-Control Studies; Cell Cycle Proteins; Cell Transformation, Neoplastic; Colon; Colonic Neoplasms; DNA (Cytosine-5-)-Methyltransferase 1; DNA Methylation; Databases, Genetic; Disease Models, Animal; Fenofibrate; Gene Expression Regulation, Neoplastic; Humans; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Nuclear Proteins; PPAR alpha; Protein-Arginine N-Methyltransferases; Signal Transduction
PubMed: 31154022
DOI: 10.1053/j.gastro.2019.05.057 -
Journal of Experimental & Clinical... Jan 2021Alcohol-induced intestinal dysbiosis disrupts and inflammatory responses are essential in the development of alcoholic fatty liver disease (AFLD). Here, we investigated...
Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance.
BACKGROUND
Alcohol-induced intestinal dysbiosis disrupts and inflammatory responses are essential in the development of alcoholic fatty liver disease (AFLD). Here, we investigated the effects of Fmo5 on changes in enteric microbiome composition in a model of AFLD and dissected the pathogenic role of Fmo5 in AFLD-induced liver pathology.
METHODS
The expression profile data of GSE8006 and GSE40334 datasets were downloaded from the GEO database. The WGCNA approach allowed us to investigate the AFLD-correlated module. DEGs were used to perform KEGG pathway enrichment analyses. Four PPI networks were constructed using the STRING database and visualized using Cytoscape software. The Cytohubba plug-in was used to identify the hub genes. Western blot and immunohistochemistry assays were used to detect protein expression. ELISA assay was used to detect the levels of serum inflammatory cytokines. Lipid droplets in the cytoplasm were observed using Oil Red O staining. Apoptosis was detected using a TUNEL assay and flow cytometry analysis. ROS levels were detected using flow cytometry analysis. Nuclear translocation of NF-κB p65 was observed using immunofluorescence staining. Co-immunoprecipitation was used to detect the co-expression of PPARα and Fmo5 in L02 cells. 16S rDNA sequencing defined the bacterial communities in mice with AFLD.
RESULTS
Fmo5 is a key DEG and is closely associated with the gut microbiota and PPAR signaling pathway. Gut microbiome function in AFLD was significantly related to the PPAR signaling pathway. AFLD induced shifts in various bacterial phyla in the cecum, including a reduction in Bacteroidetes and increased Firmicutes. Fmo5 and PPARα co-expression in cell and animal models with AFLD, which decreased significantly. Silencing of Fmo5 and PPARα aggravated the functions of AFLD inducing apoptosis and inflammatory response, promoting liver injury, and activating the NF-κB signaling pathway in vivo and in vitro. The NF-κB inhibitor abolished the functions of silencing of Fmo5 and PPARα promoting AFLD-induced apoptosis, inflammatory response, and liver injury.
CONCLUSION
Our data indicated that the co-expression of Fmo5 and PPARα was involved in AFLD-related gut microbiota composition and alleviated AFLD-induced liver injury, apoptosis, and inflammatory response by inhibiting the nuclear translocation of NF-κB p65 to inhibit the NF-κB signaling pathway.
Topics: Animals; Disease Models, Animal; Fatty Liver, Alcoholic; Gastrointestinal Microbiome; Humans; Male; Mice; NF-kappa B; Oxygenases; PPAR alpha; Signal Transduction; Transfection
PubMed: 33413501
DOI: 10.1186/s13046-020-01782-w -
The Journal of Experimental Medicine May 2021Meteorin-like/Meteorin-β (Metrnl/Metrnβ) is a secreted protein produced by skeletal muscle and adipose tissue that exerts metabolic actions that improve glucose...
Meteorin-like/Meteorin-β (Metrnl/Metrnβ) is a secreted protein produced by skeletal muscle and adipose tissue that exerts metabolic actions that improve glucose metabolism. The role of Metrnβ in cardiac disease is completely unknown. Here, we show that Metrnβ-null mice exhibit asymmetrical cardiac hypertrophy, fibrosis, and enhanced signs of cardiac dysfunction in response to isoproterenol-induced cardiac hypertrophy and aging. Conversely, adeno-associated virus-mediated specific overexpression of Metrnβ in the heart prevents the development of cardiac remodeling. Furthermore, Metrnβ inhibits cardiac hypertrophy development in cardiomyocytes in vitro, indicating a direct effect on cardiac cells. Antibody-mediated blockage of Metrnβ in cardiomyocyte cell cultures indicated an autocrine action of Metrnβ on the heart, in addition to an endocrine action. Moreover, Metrnβ is highly produced in the heart, and analysis of circulating Metrnβ concentrations in a large cohort of patients reveals that it is a new biomarker of heart failure with an independent prognostic value.
Topics: Animals; Animals, Newborn; Blood Pressure; Cardiomegaly; Cardiotonic Agents; Cells, Cultured; Disease Models, Animal; Echocardiography; Gene Expression Regulation; Heart Failure; Humans; Male; Mice, Inbred C57BL; Mice, Knockout; Muscle, Skeletal; Myocytes, Cardiac; Nerve Growth Factors; PPAR alpha; Mice
PubMed: 33635944
DOI: 10.1084/jem.20201206 -
International Journal of Molecular... Aug 2023Osteoarthritis (OA) represents the foremost degenerative joint disease observed in a clinical context. The escalating issue of population aging significantly exacerbates... (Review)
Review
Osteoarthritis (OA) represents the foremost degenerative joint disease observed in a clinical context. The escalating issue of population aging significantly exacerbates the prevalence of OA, thereby imposing an immense annual economic burden on societies worldwide. The current therapeutic landscape falls short in offering reliable pharmaceutical interventions and efficient treatment methodologies to tackle this growing problem. However, the scientific community continues to dedicate significant efforts towards advancing OA treatment research. Contemporary studies have discovered that the progression of OA may be slowed through the strategic influence on peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated receptors within the nuclear hormone receptor family. The three distinctive subtypes-PPARα, PPARβ/δ, and PPARγ-find expression across a broad range of cellular terminals, thus managing a multitude of intracellular metabolic operations. The activation of PPARγ and PPARα has been shown to efficaciously modulate the NF-κB signaling pathway, AP-1, and other oxidative stress-responsive signaling conduits, leading to the inhibition of inflammatory responses. Furthermore, the activation of PPARγ and PPARα may confer protection to chondrocytes by exerting control over its autophagic behavior. In summation, both PPARγ and PPARα have emerged as promising potential targets for the development of effective OA treatments.
Topics: Humans; PPAR gamma; PPAR alpha; PPAR-beta; PPAR delta; Osteoarthritis
PubMed: 37685944
DOI: 10.3390/ijms241713137 -
Cardiovascular Research Aug 2023The metabolic failure of macrophages to adequately process lipid is central to the aetiology of atherosclerosis. Here, we examine the role of macrophage...
AIMS
The metabolic failure of macrophages to adequately process lipid is central to the aetiology of atherosclerosis. Here, we examine the role of macrophage angiotensin-converting enzyme (ACE) in a mouse model of PCSK9-induced atherosclerosis.
METHODS AND RESULTS
Atherosclerosis in mice was induced with AAV-PCSK9 and a high-fat diet. Animals with increased macrophage ACE (ACE 10/10 mice) have a marked reduction in atherosclerosis vs. WT mice. Macrophages from both the aorta and peritoneum of ACE 10/10 express increased PPARα and have a profoundly altered phenotype to process lipids characterized by higher levels of the surface scavenger receptor CD36, increased uptake of lipid, increased capacity to transport long chain fatty acids into mitochondria, higher oxidative metabolism and lipid β-oxidation as determined using 13C isotope tracing, increased cell ATP, increased capacity for efferocytosis, increased concentrations of the lipid transporters ABCA1 and ABCG1, and increased cholesterol efflux. These effects are mostly independent of angiotensin II. Human THP-1 cells, when modified to express more ACE, increase expression of PPARα, increase cell ATP and acetyl-CoA, and increase cell efferocytosis.
CONCLUSION
Increased macrophage ACE expression enhances macrophage lipid metabolism, cholesterol efflux, efferocytosis, and it reduces atherosclerosis. This has implications for the treatment of cardiovascular disease with angiotensin II receptor antagonists vs. ACE inhibitors.
Topics: Humans; Animals; Mice; Proprotein Convertase 9; PPAR alpha; Lipid Metabolism; Cholesterol; Macrophages; Atherosclerosis; Angiotensins; Adenosine Triphosphate; ATP Binding Cassette Transporter 1
PubMed: 37225143
DOI: 10.1093/cvr/cvad082 -
Biomolecules & Biomedicine May 2023Inflammation contributes to the pathogenesis of several diseases. Fenofibrate, known as a peroxisome proliferator-activated receptor - α (PPAR-α) agonist, is a classic... (Review)
Review
Inflammation contributes to the pathogenesis of several diseases. Fenofibrate, known as a peroxisome proliferator-activated receptor - α (PPAR-α) agonist, is a classic drug for treating hyperlipidemia. In addition to its lipid-lowering effect, fenofibrate has also been reported to exert anti-inflammatory effects with complicated underlying mechanisms of action. In general, the anti-inflammatory effect of fenofibrate is secondary to its lipid-lowering effect, especially for the inflammation caused by hyperlipidemia in the circulatory system. Some anti-inflammatory actions may also come from its regulatory effects on intracellular lipid metabolism by activating PPAR-α. In addition, some roles in anti-inflammation might be mediated by its direct regulation of inflammatory signaling pathways. In order to understand anti-inflammatory activities and the underlying mechanisms of fenofibrate action in disease better, we herein reviewed and discussed the anti-inflammatory roles and its subserving mechanisms in various diseases of different organ systems. Thus, this review offers insights into the optimal use of fenofibrate in the clinical setting.
Topics: Humans; Fenofibrate; PPAR alpha; Anti-Inflammatory Agents; Inflammation; Hyperlipidemias; Lipids
PubMed: 36724021
DOI: 10.17305/bb.2022.8534 -
Cells Aug 2022Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and... (Review)
Review
Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and heterodimerization with retinoic X receptors. Physiological ligands include fatty acids and fatty-acid-derived compounds with low specificity for the different PPAR subtypes (alpha, beta/delta, and gamma). For each of the PPAR subtypes, specific pharmacological agonists and antagonists, as well as pan-agonists, are available. In agreement with their natural ligands, PPARs are mainly focused on as targets for the treatment of metabolic syndrome and its associated complications. Nevertheless, many publications are available that implicate PPARs in malignancies. In several instances, they are controversial for very similar models. Thus, to better predict the potential use of PPAR modulators for personalized medicine in therapies against malignancies, it seems necessary and timely to review the three PPARs in relation to the didactic concept of cancer hallmark capabilities. We previously described the functions of PPAR beta/delta with respect to the cancer hallmarks and reviewed the implications of all PPARs in angiogenesis. Thus, the current review updates our knowledge on PPAR beta and the hallmarks of cancer and extends the concept to PPAR alpha and PPAR gamma.
Topics: Fatty Acids; Humans; Ligands; Neoplasms; PPAR alpha; PPAR delta; PPAR-beta; Peroxisome Proliferator-Activated Receptors
PubMed: 35954274
DOI: 10.3390/cells11152432 -
Cells Feb 2023Peroxisome proliferator-activated receptors (PPARs) α, β, and γ are nuclear receptors that orchestrate the transcriptional regulation of genes involved in a variety... (Review)
Review
Peroxisome proliferator-activated receptors (PPARs) α, β, and γ are nuclear receptors that orchestrate the transcriptional regulation of genes involved in a variety of biological responses, such as energy metabolism and homeostasis, regulation of inflammation, cellular development, and differentiation. The many roles played by the PPAR signaling pathways indicate that PPARs may be useful targets for various human diseases, including metabolic and inflammatory conditions and tumors. Accumulating evidence suggests that each PPAR plays prominent but different roles in viral, bacterial, and parasitic infectious disease development. In this review, we discuss recent PPAR research works that are focused on how PPARs control various infections and immune responses. In addition, we describe the current and potential therapeutic uses of PPAR agonists/antagonists in the context of infectious diseases. A more comprehensive understanding of the roles played by PPARs in terms of host-pathogen interactions will yield potential adjunctive personalized therapies employing PPAR-modulating agents.
Topics: Humans; Receptors, Cytoplasmic and Nuclear; Gene Expression Regulation; PPAR alpha; Inflammation; Communicable Diseases
PubMed: 36831317
DOI: 10.3390/cells12040650 -
Frontiers in Endocrinology 2022Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that is involved in lipid metabolism of various tissues. Different... (Review)
Review
Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that is involved in lipid metabolism of various tissues. Different metabolites of fatty acids and agonists like fibrates activate PPARα for its transactivative or repressive function. PPARα is known to affect diverse human diseases, and we focus on advanced studies of its transcriptional regulation in these diseases. In MAFLD, PPARα shows a protective function with its upregulation of lipid oxidation and mitochondrial biogenesis and transcriptional repression of inflammatory genes, which is similar in Alzheimer's disease and cardiovascular disease. Activation of PPARα also prevents the progress of diabetes complications; however, its role in diabetes and cancers remains uncertain. Some PPARα-specific agonists, such as Wy14643 and fenofibrate, have been applied in metabolic syndrome treatment, which might own potential in wider application. Future studies may further explore the functions and interventions of PPARα in cancer, diabetes, immunological diseases, and neurodegenerative disease.
Topics: Humans; Cardiovascular Diseases; Fenofibrate; Metabolic Syndrome; Neurodegenerative Diseases; PPAR alpha
PubMed: 36589809
DOI: 10.3389/fendo.2022.1074911 -
Cell Reports Jul 2022This study underlines the importance of treadmill exercise in reducing α-synuclein (α-syn) spreading in the A53T brain and protecting nigral dopaminergic neurons....
This study underlines the importance of treadmill exercise in reducing α-synuclein (α-syn) spreading in the A53T brain and protecting nigral dopaminergic neurons. Preformed α-syn fibril (PFF) seeding in the internal capsule of young A53T α-syn mice leads to increased spreading of α-syn to substantia nigra and motor cortex and concomitant loss of nigral dopaminergic neurons. However, regular treadmill exercise decreases α-syn spreading in the brain and protects nigral dopaminergic neurons in PFF-seeded mice. Accordingly, treadmill exercise also mitigates α-synucleinopathy in aged A53T mice. While investigating this mechanism, we have observed that treadmill exercise induces the activation of peroxisome proliferator-activated receptor α (PPARα) in the brain to stimulate lysosomal biogenesis via TFEB. Accordingly, treadmill exercise remains unable to stimulate TFEB and reduce α-synucleinopathy in A53T mice lacking PPARα, and fenofibrate, a prototype PPARα agonist, reduces α-synucleinopathy. These results delineate a beneficial function of treadmill exercise in reducing α-syn spreading in the brain via PPARα.
Topics: Animals; Disease Models, Animal; Dopaminergic Neurons; Mice; PPAR alpha; Physical Conditioning, Animal; Substantia Nigra; Synucleinopathies; alpha-Synuclein
PubMed: 35830804
DOI: 10.1016/j.celrep.2022.111058