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Ecotoxicology and Environmental Safety Feb 2022A growing body of evidence associated particulate matter (PM) exposure with lipid metabolism disorders, yet, the underlying mechanism remains to be elucidated. Among the...
A growing body of evidence associated particulate matter (PM) exposure with lipid metabolism disorders, yet, the underlying mechanism remains to be elucidated. Among the major lipid metabolism modulators, peroxisome proliferator-activated receptor (PPAR) alpha plays an important role. In the current study, an individually ventilated cage (IVC) system was used to expose C57/B6 mice to real-ambient PM for six weeks, with or without co-treatment of PPAR alpha agonist WY14,643. The general parameters, liver and adipose tissue pathology, serum lipids, metal deposition and lipid profile of liver were assessed. The results indicated that six weeks of real-ambient PM exposure induced dyslipidemia, including increased serum triglycerides (TG) and decreased high density lipoprotein cholesterol (HDL-C) level, along with steatosis in liver, increased size of adipocytes in white adipose tissue (WAT) and whitening of brown adipose tissue (BAT). ICP-MS results indicated increased Cr and As deposition in liver. Lipidomics analysis revealed that glycerophospholipids and cytochrome P450 pathway were most significantly affected by PM exposure. Several lipid metabolism-related genes, including CYP4A14 in liver and UCP1 in BAT were downregulated following PM exposure. WY14,643 treatment alleviated PM-induced dyslipidemia, liver steatosis and whitening of BAT, while enhancing CD36, SLC27A1, CYP4A14 and UCP1 expression. In conclusion, PPAR alpha pathway participates in PM-induced lipid metabolism disorder, PPAR alpha agonist WY14,643 treatment exerted protective effects on PM-induced dyslipidemia, liver steatosis and whitening of BAT, but not on increased adipocyte size of WAT.
Topics: Adipose Tissue, Brown; Animals; Lipid Metabolism; Lipid Metabolism Disorders; Mice; PPAR alpha; Particulate Matter; Peroxisome Proliferators
PubMed: 35007830
DOI: 10.1016/j.ecoenv.2022.113173 -
Asia Pacific Journal of Clinical... 2008In Western culture, excess visceral fat accumulation or obesity has reached epidemic proportions, resulting in metabolic syndrome. However, more than 10 years of... (Review)
Review
In Western culture, excess visceral fat accumulation or obesity has reached epidemic proportions, resulting in metabolic syndrome. However, more than 10 years of research has shown that adipocytes also function as endocrine cells that release various bioactive substances, so called "adipocytokines or adipokines", that play a major role in the regulation of food intake, insulin sensitivity, energy metabolism, and the vascular microenvironment. Adiponectin, an adipocytokine, is considered to improve insulin sensitivity. Recently, monocyte chemoattractant protein (MCP)-1 has been reported to be a novel adipocytokine involved in the development of obesity-associated insulin resistance and atherosclerosis. Nuclear receptors, especially peroxisome proliferator-activated receptor-alpha (PPAR alpha) and PPAR gamma are ligand-activated transcription factors that regulate the metabolism of glucose and lipids. PPAR gamma is strongly expressed in adipocytes and plays a significant role in the transcriptional activation of adipocytokines including adiponectin. PPAR alpha, another PPAR isoform, is involved in the control of lipid metabolism in the liver and skeletal muscle. PPAR alpha activation causes lipid clearance via beta-oxidation enhancement. We showed that various dietary terpenoids and other natural ingredients regulate the transcription of PPAR target genes, induces the expression and secretion of adiponectin, and inhibits those of MCP-1 in adipocytes and beta-oxidation in liver. These findings indicate that dietary factor acts as an agonist of PPARs and is a valuable medical and food component for the gradual improvement of metabolic syndrome.
Topics: Adipokines; Adiponectin; Adipose Tissue; Humans; Insulin Resistance; Lipid Metabolism; Metabolic Syndrome; Obesity; PPAR alpha; PPAR gamma
PubMed: 18296319
DOI: No ID Found -
Addiction Biology Jul 2016Oleoylethanolamide (OEA) is a satiety factor that controls motivational responses to dietary fat. Here we show that alcohol administration causes the release of OEA in...
Oleoylethanolamide (OEA) is a satiety factor that controls motivational responses to dietary fat. Here we show that alcohol administration causes the release of OEA in rodents, which in turn reduces alcohol consumption by engaging peroxisome proliferator-activated receptor-alpha (PPAR-α). This effect appears to rely on peripheral signaling mechanisms as alcohol self-administration is unaltered by intracerebral PPAR-α agonist administration, and the lesion of sensory afferent fibers (by capsaicin) abrogates the effect of systemically administered OEA on alcohol intake. Additionally, OEA is shown to block cue-induced reinstatement of alcohol-seeking behavior (an animal model of relapse) and reduce the severity of somatic withdrawal symptoms in alcohol-dependent animals. Collectively, these findings demonstrate a homeostatic role for OEA signaling in the behavioral effects of alcohol exposure and highlight OEA as a novel therapeutic target for alcohol use disorders and alcoholism.
Topics: Alcohol Drinking; Alcoholism; Animals; Disease Models, Animal; Endocannabinoids; Male; Mice; Oleic Acids; PPAR alpha; Rats, Wistar; Satiety Response; Signal Transduction
PubMed: 26037332
DOI: 10.1111/adb.12276 -
Journal of Ethnopharmacology Apr 2024Dendrobium nobile Lindl. (DNL) is a traditional Chinese ethnobotanical herb. Dendrobine (DNE) has been designated as a quality indicator for DNL in the Chinese...
ETHNOPHARMACOLOGICAL RELEVANCE
Dendrobium nobile Lindl. (DNL) is a traditional Chinese ethnobotanical herb. Dendrobine (DNE) has been designated as a quality indicator for DNL in the Chinese Pharmacopoeia. DNE exhibits various pharmacological activities, including the reduction of blood lipids, regulation of blood sugar levels, as well as anti-inflammatory and antioxidant properties.
AIM OF THE STUDY
The objective of this study is to explore the impact of DNE on lipid degeneration in nonalcoholic fatty liver disease (NAFLD) liver cells and elucidate its specific mechanism. The findings aim to offer theoretical support for the development of drugs related to DNL.
MATERIALS AND METHODS
We utilized male C57BL/6J mice, aged 6 weeks old, to establish a NAFLD model. This model allowed us to assess the impact of DNE on liver pathology and lipid levels in NAFLD mice. We investigated the mechanism of DNE's regulation of lipid metabolism through RNA-seq analysis. Furthermore, a NAFLD model was established using HepG2 cells to further evaluate the impact of DNE on the pathological changes of NAFLD liver cells. The potential mechanism of DNE's improvement was rapidly elucidated using HT-qPCR technology. These results were subsequently validated using mouse liver samples. Following the in vitro activation or inhibition of PPARα function, we observed changes in DNE's ability to ameliorate pathological changes in NAFLD hepatocytes. This mechanism was further verified through RT-qPCR and Western blot analysis.
RESULTS
DNE demonstrated a capacity to enhance serum TC, TG, and liver TG levels in mice, concurrently mitigating liver lipid degeneration. RNA-seq analysis unveiled that DNE primarily modulates the expression of genes related to metabolic pathways in mouse liver. Utilizing HT-qPCR technology, it was observed that DNE markedly regulates the expression of genes associated with the PPAR signaling pathway in liver cells. Consistency was observed in the in vivo data, where DNE significantly up-regulated the expression of PPARα mRNA and its protein level in mouse liver. Additionally, the expression of fatty acid metabolism-related genes (ACOX1, CPT2, HMGCS2, LPL), regulated by PPARα, was significantly elevated following DNE treatment. In vitro experiments further demonstrated that DNE notably ameliorated lipid deposition, peroxidation, and inflammation levels in NAFLD hepatocytes, particularly when administered in conjunction with fenofibrate. Notably, the PPARα inhibitor GW6471 attenuated these effects of DNE.
CONCLUSIONS
In summary, DNE exerts its influence on the expression of genes associated with downstream fat metabolism by regulating PPARα. This regulatory mechanism enhances liver lipid metabolism, mitigates lipid degeneration in hepatocytes, and ultimately ameliorates the pathological changes in NAFLD hepatocytes.
Topics: Male; Mice; Animals; Non-alcoholic Fatty Liver Disease; PPAR alpha; Mice, Inbred C57BL; Liver; Lipid Metabolism; Lipids; Alkaloids
PubMed: 38171466
DOI: 10.1016/j.jep.2023.117684 -
Cells Mar 2021Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors including PPARα, PPARγ, and PPARβ/δ, acting as transcription factors to... (Review)
Review
Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors including PPARα, PPARγ, and PPARβ/δ, acting as transcription factors to regulate the expression of a plethora of target genes involved in metabolism, immune reaction, cell differentiation, and a variety of other cellular changes and adaptive responses. PPARs are activated by a large number of both endogenous and exogenous lipid molecules, including phyto- and endo-cannabinoids, as well as endocannabinoid-like compounds. In this view, they can be considered an extension of the endocannabinoid system. Besides being directly activated by cannabinoids, PPARs are also indirectly modulated by receptors and enzymes regulating the activity and metabolism of endocannabinoids, and, vice versa, the expression of these receptors and enzymes may be regulated by PPARs. In this review, we provide an overview of the crosstalk between cannabinoids and PPARs, and the importance of their reciprocal regulation and modulation by common ligands, including those belonging to the extended endocannabinoid system (or "endocannabinoidome") in the control of major physiological and pathophysiological functions.
Topics: Animals; Endocannabinoids; Gene Expression Regulation; Humans; Ligands; Lipid Metabolism; Mice; Mice, Knockout; Models, Molecular; PPAR alpha; PPAR delta; PPAR gamma; PPAR-beta; Receptors, Cannabinoid; Signal Transduction; Transcription, Genetic
PubMed: 33799988
DOI: 10.3390/cells10030586 -
Epilepsia Nov 2008Peroxisome proliferator-activated receptor alpha (PPARalpha) is a drug/fatty acid-activated trans cription factor involved in the starvation response, and is thus... (Review)
Review
Peroxisome proliferator-activated receptor alpha (PPARalpha) is a drug/fatty acid-activated trans cription factor involved in the starvation response, and is thus relevant to the ketogenic diet (KD). This article summarizes research indicating the role of PPARalpha in central and peripheral nervous system function with particular reference to downstream targets relevant to anticonvulsant action.
Topics: Animals; Anticonvulsants; Brain; Diet, Ketogenic; Epilepsy; Humans; PPAR alpha
PubMed: 19049593
DOI: 10.1111/j.1528-1167.2008.01840.x -
Laboratory Investigation; a Journal of... Dec 2004The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to...
The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid and thyroid hormone receptors. The aim of the present study was to examine the effects of endogenous and exogenous PPAR-alpha ligand on the development of experimental colitis. To address this question, we used an experimental model of colitis, induced by dinitrobenzene sulfonic acid (DNBS). When compared to DNBS-treated PPAR-alpha wild-type (WT) mice, DNBS-treated PPAR-alpha knockout mice (PPAR-alphaKO) mice experienced a higher rate of the extent and severity of the histological signs of colon injury. After administration of DNBS PPAR-alphaWT mice experienced hemorrhagic diarrhea, weight loss and large areas of necrosis in the mucosa of the colon were also observed. Neutrophil infiltration was associated with upregulation of ICAM-1. Immunohistochemistry for nitrotyrosine showed an intense staining in the inflamed colon. Absence of a functional PPAR-alpha gene in PPAR-alphaKO mice resulted in a significant augmentation of all the above-described parameters. On the contrary, the treatment of PPAR-alphaWT with Wy-14643 (1 mg/kg daily i.p) significantly reduced: (i) the degree of hemorrhagic diarrhea and weight loss, (ii) the degree of colon injury, (iii) the rise in MPO activity (mucosa), (iv) the increase in staining (immunohistochemistry) for nitrotyrosine, as well as (v) the upregulation of ICAM-1 caused by DNBS in the colon. In order to elucidate whether the protective effects of Wy-14643 is related to activation of the PPAR-alpha receptor, we also investigated the effect the of Wy-14643 treatment on PPAR-alpha-deficient mice. The absence of the PPAR-alpha receptor significantly abolished the protective effect of the PPAR-alpha agonist against DNBS-induced colitis. Thus, endogenous and exogenous PPAR-alpha ligands reduce the degree of colitis caused by DNBS. We propose that PPAR-alpha ligand may be useful in the treatment of inflammatory bowel disease.
Topics: Animals; Dinitrofluorobenzene; Disease Models, Animal; Inflammatory Bowel Diseases; Ligands; Mice; Mice, Knockout; PPAR alpha
PubMed: 15492755
DOI: 10.1038/labinvest.3700185 -
Biochemical and Biophysical Research... Feb 2023Fibroblast growth factor 21 (FGF21) has emerged as a metabolic regulator that exerts potent anti-diabetic and lipid-lowering effects in animal models of obesity and type...
Fibroblast growth factor 21 (FGF21) has emerged as a metabolic regulator that exerts potent anti-diabetic and lipid-lowering effects in animal models of obesity and type 2 diabetes, showing a protective role in fatty liver disease and hepatocellular carcinoma progression. Hepatic expression of FGF21 is regulated by PPARα and is induced by fasting. Ablation of FoxO1 in liver has been shown to increase FGF21 expression in hyperglycemia. To better understand the role of FOXO1 in the regulation of FGF21 expression we have modified HepG2 human hepatoma cells to overexpress FoxO1 and PPARα. Here we show that FoxO1 represses PPARα-mediated FGF21 induction, and that the repression acts on the FGF21 gene promoter without affecting other PPARα target genes. Additionally, we demonstrate that FoxO1 physically interacts with PPARα and that FoxO1/3/4 depletion in skeletal muscle contributes to increased Fgf21 tissue levels. Taken together, these data indicate that FOXO1 is a PPARα-interacting protein that antagonizes PPARα activity on the FGF21 promoter. Because other PPARα target genes remained unaffected, these results suggest a highly specific mechanism implicated in FGF21 regulation. We conclude that FGF21 can be specifically modulated by FOXO1 in a PPARα-dependent manner.
Topics: Animals; Humans; PPAR alpha; Diabetes Mellitus, Type 2; Liver; Fibroblast Growth Factors; Gene Expression; Gene Expression Regulation; Forkhead Box Protein O1
PubMed: 36640666
DOI: 10.1016/j.bbrc.2023.01.012 -
Toxicology Jan 2022Human exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous, with mixtures of PFAS detected in drinking water, food, household dust, and other exposure... (Comparative Study)
Comparative Study
Human exposure to per- and polyfluoroalkyl substances (PFAS) is ubiquitous, with mixtures of PFAS detected in drinking water, food, household dust, and other exposure sources. Animal toxicity studies and human epidemiology indicate that PFAS may act through shared mechanisms including activation of peroxisome proliferator activated receptor α (PPARα). However, the effect of PFAS mixtures on human relevant molecular initiating events remains an important data gap in the PFAS literature. Here, we tested the ability of modeling approaches to predict the effect of diverse PPARα ligands on receptor activity using Cos7 cells transiently transfected with a full length human PPARα (hPPARα) expression construct and a peroxisome proliferator response element-driven luciferase reporter. Cells were treated for 24 h with two full hPPARα agonists (pemafibrate and GW7647), a full and a partial hPPARα agonist (pemafibrate and mono(2-ethylhexyl) phthalate), or a full hPPARα agonist and a competitive antagonist (pemafibrate and GW6471). Receptor activity was modeled with three additive approaches: effect summation, relative potency factors (RPF), and generalized concentration addition (GCA). While RPF and GCA accurately predicted activity for mixtures of full hPPARα agonists, only GCA predicted activity for full and partial hPPARα agonists and a full agonist and antagonist. We then generated concentration response curves for seven PFAS, which were well-fit with three-parameter Hill functions. The four perfluorinated carboxylic acids (PFCA) tended to act as full hPPARα agonists while the three perfluorinated sulfonic acids (PFSA) tended to act as partial agonists that varied in efficacy between 28-67 % of the full agonist, positive control level. GCA and RPF performed equally well at predicting the effects of mixtures with three PFCAs, but only GCA predicted experimental activity with mixtures of PFSAs and a mixture of PFCAs and PFSAs at ratios found in the general population. We conclude that of the three approaches, GCA most accurately models the effect of PFAS mixtures on hPPARα activity in vitro. Understanding the differences in efficacy with which PFAS activate hPPARα is essential for accurately predicting the effects of PFAS mixtures. As PFAS can activate multiple nuclear receptors, future analyses should examine mixtures effects in intact cells where multiple molecular initiating events contribute to proximate effects and functional changes.
Topics: Animals; COS Cells; Carboxylic Acids; Chlorocebus aethiops; Dose-Response Relationship, Drug; Drug Partial Agonism; Hydrocarbons, Fluorinated; Models, Molecular; Molecular Structure; PPAR alpha; Signal Transduction; Structure-Activity Relationship; Sulfonic Acids
PubMed: 34743024
DOI: 10.1016/j.tox.2021.153024 -
Mediators of Inflammation 2013Neuropathic syndromes which are evoked by lesions to the peripheral or central nervous system are extremely difficult to treat, and available drugs rarely joint an...
Neuropathic syndromes which are evoked by lesions to the peripheral or central nervous system are extremely difficult to treat, and available drugs rarely joint an antihyperalgesic with a neurorestorative effect. N-Palmitoylethanolamine (PEA) exerts antinociceptive effects in several animal models and inhibits peripheral inflammation in rodents. Aimed to evaluate the antineuropathic properties of PEA, a damage of the sciatic nerve was induced in mice by chronic constriction injury (CCI) and a subcutaneous daily treatment with 30 mg kg(-1) PEA was performed. On the day 14, PEA prevented pain threshold alterations. Histological studies highlighted that CCI induced oedema and an important infiltrate of CD86 positive cells in the sciatic nerve. Moreover, osmicated preparations revealed a decrease in axon diameter and myelin thickness. Repeated treatments with PEA reduced the presence of oedema and macrophage infiltrate, and a significant higher myelin sheath, axonal diameter, and a number of fibers were observable. In PPAR- α null mice PEA treatment failed to induce pain relief as well as to rescue the peripheral nerve from inflammation and structural derangement. These results strongly suggest that PEA, via a PPAR- α -mediated mechanism, can directly intervene in the nervous tissue alterations responsible for pain, starting to prevent macrophage infiltration.
Topics: Amides; Animals; Blotting, Western; Endocannabinoids; Ethanolamines; Hyperalgesia; Immunohistochemistry; Male; Mice; Mice, Knockout; PPAR alpha; Palmitic Acids; Peripheral Nervous System Diseases
PubMed: 23533304
DOI: 10.1155/2013/328797