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The FEBS Journal Dec 2022Rewiring metabolism to sustain cell growth, division, and survival is the most prominent feature of cancer cells. In particular, dysregulated lipid metabolism in cancer... (Review)
Review
Rewiring metabolism to sustain cell growth, division, and survival is the most prominent feature of cancer cells. In particular, dysregulated lipid metabolism in cancer has received accumulating interest, since lipid molecules serve as cell membrane structure components, secondary signaling messengers, and energy sources. Given the critical role of immune cells in host defense against cancer, recent studies have revealed that immune cells compete for nutrients with cancer cells in the tumor microenvironment and accordingly develop adaptive metabolic strategies for survival at the expense of compromised immune functions. Among these strategies, lipid metabolism reprogramming toward fatty acid oxidation is closely related to the immunosuppressive phenotype of tumor-infiltrated immune cells, including macrophages and dendritic cells. Therefore, it is important to understand the lipid-mediated crosstalk between cancer cells and immune cells in the tumor microenvironment. Peroxisome proliferator-activated receptors (PPARs) consist of a nuclear receptor family for lipid sensing, and one of the family members PPARα is responsible for fatty acid oxidation, energy homeostasis, and regulation of immune cell functions. In this review, we discuss the emerging role of PPARα-associated metabolic-immune regulation in tumor-infiltrated immune cells, and key metabolic events and pathways involved, as well as their influences on antitumor immunity.
Topics: Humans; PPAR alpha; Receptors, Cytoplasmic and Nuclear; Neoplasms; Lipid Metabolism; Fatty Acids; Lipids; Tumor Microenvironment
PubMed: 34480827
DOI: 10.1111/febs.16181 -
Theranostics 2022Leucine-rich repeat-containing G protein-coupled receptor 5 () is a target gene of Wnt/β-Catenin which plays a vital role in hepatic development and regeneration....
Leucine-rich repeat-containing G protein-coupled receptor 5 () is a target gene of Wnt/β-Catenin which plays a vital role in hepatic development and regeneration. However, the regulation of gene and the fate of cells in hepatic physiology and pathology are little known. This study aims to clarify the effect of metabolic nuclear receptors on cell fate in liver. We performed cell experiments with primary hepatocytes, Hep 1-6, Hep G2, and Huh 7 cells, and animal studies with wild-type (WT), farnesoid X receptor (FXR) knockout mice, peroxisome proliferator-activated receptor α (PPARα) knockout mice and -Cre; Rosa26-mTmG mice. GW4064 and CDCA were used to activate FXR. And GW7647 or Wy14643 was used for PPARα activation. Regulation of by FXR and PPARα was determined by QRT-PCR, western blot (WB) and RNAscope hybridization (ISH) and immunofluorescence (IF), luciferase reporter assay, electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). Diethyl 1,4-dihydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) diet was used to induce liver injury. Pharmacologic activation of FXR induced expression, whereas activation of PPARα suppressed expression. Furthermore, FXR and PPARα competed for binding to shared site on promoter with opposite transcriptional outputs. DDC diet triggered the transition of cells from resting state to proliferation. FXR activation enhanced cell expansion mainly by symmetric cell division, but PPARα activation prevented cell proliferation along with asymmetric cell division. Our findings unravel the opposite regulatory effects of FXR and PPARα on cell fate in liver under physiological and pathological conditions, which will greatly assist novel therapeutic development targeting nuclear receptors.
Topics: Animals; Leucine; Liver; Mice; Mice, Knockout; PPAR alpha; Receptors, Cytoplasmic and Nuclear; Receptors, G-Protein-Coupled; Signal Transduction; beta Catenin
PubMed: 36168631
DOI: 10.7150/thno.74194 -
Experimental & Molecular Medicine Dec 2019Mycobacterium tuberculosis (Mtb) is a major causal pathogen of human tuberculosis (TB), which is a serious health burden worldwide. The demand for the development of an... (Review)
Review
Mycobacterium tuberculosis (Mtb) is a major causal pathogen of human tuberculosis (TB), which is a serious health burden worldwide. The demand for the development of an innovative therapeutic strategy to treat TB is high due to drug-resistant forms of TB. Autophagy is a cell-autonomous host defense mechanism by which intracytoplasmic cargos can be delivered and then destroyed in lysosomes. Previous studies have reported that autophagy-activating agents and small molecules may be beneficial in restricting intracellular Mtb infection, even with multidrug-resistant Mtb strains. Recent studies have revealed the essential roles of host nuclear receptors (NRs) in the activation of the host defense through antibacterial autophagy against Mtb infection. In particular, we discuss the function of estrogen-related receptor (ERR) α and peroxisome proliferator-activated receptor (PPAR) α in autophagy regulation to improve host defenses against Mtb infection. Despite promising findings relating to the antitubercular effects of various agents, our understanding of the molecular mechanism by which autophagy-activating agents suppress intracellular Mtb in vitro and in vivo is lacking. An improved understanding of the antibacterial autophagic mechanisms in the innate host defense will eventually lead to the development of new therapeutic strategies for human TB.
Topics: Animals; Autophagy; Humans; Models, Biological; Mycobacterium; PPAR alpha
PubMed: 31827065
DOI: 10.1038/s12276-019-0290-7 -
Current Neuropharmacology 2022Peroxisome proliferator-activated receptors (PPARs) activity has significant implications for the development of novel therapeutic modalities against neurodegenerative... (Review)
Review
Peroxisome proliferator-activated receptors (PPARs) activity has significant implications for the development of novel therapeutic modalities against neurodegenerative diseases. Although PPAR-α, PPAR-β/δ, and PPAR-γ nuclear receptor expressions are significantly reported in the brain, their implications in brain physiology and other neurodegenerative diseases still require extensive studies. PPAR signaling can modulate various cell signaling mechanisms involved in the cells contributing to on- and off-target actions selectively to promote therapeutic effects as well as the adverse effects of PPAR ligands. Both natural and synthetic ligands for the PPARα, PPARγ, and PPARβ/δ have been reported. PPARα (WY 14.643) and PPARγ agonists can confer neuroprotection by modulating mitochondrial dynamics through the redox system. The pharmacological effect of these agonists may deliver effective clinical responses by protecting vulnerable neurons from Aβ toxicity in Alzheimer's disease (AD) patients. Therefore, the current review delineated the ligands' interaction with 3D-PPARs to modulate neuroprotection, and also deciphered the efficacy of numerous drugs, viz. Aβ aggregation inhibitors, vaccines, and γ-secretase inhibitors against AD; this review elucidated the role of PPAR and their receptor isoforms in neural systems, and neurodegeneration in human beings. Further, we have substantially discussed the efficacy of PPREs as potent transcription factors in the brain, and the role of PPAR agonists in neurotransmission, PPAR gamma coactivator-1α (PGC-1α) and mitochondrial dynamics in neuroprotection during AD conditions. This review concludes with the statement that the development of novel PPARs agonists may benefit patients with neurodegeneration, mainly AD patients, which may help mitigate the pathophysiology of dementia, subsequently improving overall the patient's quality of life.
Topics: Alzheimer Disease; Drug Repositioning; Humans; Ligands; Mitochondrial Dynamics; Molecular Dynamics Simulation; Neurodegenerative Diseases; Oxidation-Reduction; PPAR alpha; PPAR gamma; Quality of Life; Thiazolidinediones
PubMed: 34751120
DOI: 10.2174/1570159X19666211109141330 -
International Journal of Molecular... Oct 2020Cisplatin is a chemotherapy drug widely used in the treatment of solid tumors. However, nephrotoxicity has been reported in about one-third of patients undergoing...
Cisplatin is a chemotherapy drug widely used in the treatment of solid tumors. However, nephrotoxicity has been reported in about one-third of patients undergoing cisplatin therapy. Proximal tubules are the main target of cisplatin toxicity and cellular uptake; elimination of this drug can modulate renal damage. Organic transporters play an important role in the transport of cisplatin into the kidney and organic cations transporter 2 (OCT-2) has been shown to be one of the most important transporters to play this role. On the other hand, multidrug and toxin extrusion 1 (MATE-1) transporter is the main protein that mediates the extrusion of cisplatin into the urine. Cisplatin nephrotoxicity has been shown to be enhanced by increased OCT-2 and/or reduced MATE-1 activity. Peroxisome proliferator-activated receptor alpha (PPAR-α) is the transcription factor which controls lipid metabolism and glucose homeostasis; it is highly expressed in the kidneys and interacts with both MATE-1 and OCT-2. Considering the above, we treated wild-type and PPAR-α knockout mice with cisplatin in order to evaluate the severity of nephrotoxicity. Cisplatin induced renal dysfunction, renal inflammation, apoptosis and tubular injury in wild-type mice, whereas PPAR-α deletion protected against these alterations. Moreover, we observed that cisplatin induced down-regulation of organic transporters MATE-1 and OCT-2 and that PPAR-α deletion restored the expression of these transporters. In addition, PPAR-α knockout mice at basal state showed increased MATE-1 expression and reduced OCT-2 levels. Here, we show for the first time that PPAR-α deletion protects against cisplatin nephrotoxicity and that this protection is via modulation of the organic transporters MATE-1 and OCT-2.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cisplatin; Down-Regulation; Kidney; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Organic Cation Transport Proteins; Organic Cation Transporter 2; PPAR alpha; Renal Insufficiency; Severity of Illness Index; Signal Transduction
PubMed: 33049997
DOI: 10.3390/ijms21197416 -
Poultry Science Aug 2023Cadmium (Cd) is an important environmental pollutant that causes liver damage and induces nonalcoholic fatty liver disease (NAFLD). NAFLD is a fat accumulation disease...
Cadmium (Cd) is an important environmental pollutant that causes liver damage and induces nonalcoholic fatty liver disease (NAFLD). NAFLD is a fat accumulation disease and has significant effects on the body. Melatonin (Mel) is an endogenous protective molecule with antioxidant, anti-inflammatory, antiobesity, and antiaging effects. However, whether Mel can alleviate Cd-induced NAFLD and its mechanism remains unclear. First, in vivo, we found that Mel maintained mitochondrial structure and function, inhibited oxidative stress, and reduced Cd-induced liver injury. In addition, Mel alleviated lipid accumulation in the liver induced by Cd. In this process, Mel inhibits fatty acid production and promotes fatty acid oxidation. Interestingly, Mel regulated PPAR-α expression and alleviated Cd-induced autophagy blockade. In vitro model, the oil Red O staining, and WB results showed that Mel alleviated Cd-induced lipid accumulation. In addition, RAPA was used to activate autophagy to alleviate Cd-induced lipid accumulation, and TG was used to block autophagy flux to aggravate Cd-induced autophagy accumulation. After knocking down PPAR-α, the autophagosome fusion with lysosomes, and autophagic flux was inhibited and increased Cd-induced lipid accumulation. Mel alleviates mitochondrial damage and oxidative stress, and attenuates Cd-induced NAFLD by restoring the expression of PPAR-α and restoring autophagy flux.
Topics: Animals; Non-alcoholic Fatty Liver Disease; Cadmium; Melatonin; Ducks; PPAR alpha; Chickens; Autophagy; Liver; Oxidative Stress; Fatty Acids; Lipids
PubMed: 37343350
DOI: 10.1016/j.psj.2023.102835 -
Biomolecules May 2022Peroxisome proliferator-activator receptors (PPARs) regulate lipid and glucose metabolism, control inflammatory processes, and modulate several brain functions. Three... (Review)
Review
Peroxisome proliferator-activator receptors (PPARs) regulate lipid and glucose metabolism, control inflammatory processes, and modulate several brain functions. Three PPAR isoforms have been identified, PPARα, PPARβ/δ, and PPARγ, which are expressed in different tissues and cell types. Hereinafter, we focus on PPARα involvement in the pathophysiology of neuropsychiatric and neurodegenerative disorders, which is underscored by PPARα localization in neuronal circuits involved in emotion modulation and stress response, and its role in neurodevelopment and neuroinflammation. A multiplicity of downstream pathways modulated by PPARα activation, including glutamatergic neurotransmission, upregulation of brain-derived neurotrophic factor, and neurosteroidogenic effects, encompass mechanisms underlying behavioral regulation. Modulation of dopamine neuronal firing in the ventral tegmental area likely contributes to PPARα effects in depression, anhedonia, and autism spectrum disorder (ASD). Based on robust preclinical evidence and the initial results of clinical studies, future clinical trials should assess the efficacy of PPARα agonists in the treatment of mood and neurodevelopmental disorders, such as depression, schizophrenia, and ASD.
Topics: Autism Spectrum Disorder; Humans; PPAR alpha; PPAR gamma; Signal Transduction; Transcriptional Activation
PubMed: 35625650
DOI: 10.3390/biom12050723 -
Molecular Metabolism Oct 2023Alterations in lipid metabolism are associated with aging and age-related diseases. Chaperone-mediated autophagy (CMA) is a lysosome-dependent process involved in...
OBJECTIVE
Alterations in lipid metabolism are associated with aging and age-related diseases. Chaperone-mediated autophagy (CMA) is a lysosome-dependent process involved in specific protein degradation. Heat shock cognate 71 kDa protein (Hsc70) recognizes cytosolic proteins with KFERQ motif and allows them to enter the lysosome via lysosome-associated membrane glycoprotein 2 isoform A (LAMP2A). CMA deficiency is associated with dysregulated lipid metabolism in the liver. In this study, we examined the effect of CMA on lipid metabolism in the aged liver.
METHODS
12-week-old and 88-week-old mice were employed to assess the effect of aging on hepatic CMA activity. We generated CMA-deficient mouse primary hepatocytes using siRNA for Lamp2a and liver-specific LAMP2A knockdown mice via adeno-associated viruses expressing short hairpin RNAs to investigate the influence of CMA on lipid metabolism.
RESULTS
We noted aging-induced progression toward fatty liver and a decrease in LAMP2A levels in total protein and lysosomes. The expression of genes associated with fatty acid oxidation was markedly downregulated in the aged liver, as verified in CMA-deficient mouse primary hepatocytes. In addition, the aged liver accumulated nuclear receptor corepressor 1 (NCoR1), a negative regulator of peroxisome proliferator-activated receptor α (PPARα). We found that Hsc70 binds to NCoR1 via the KFERQ motif. Lamp2a siRNA treatment accumulated NCoR1 and decreased the fatty acid oxidation rate. Pharmacological activation of CMA by AR7 treatment increased LAMP2A expression, leading to NCoR1 degradation. A liver-specific LAMP2A knockdown via adeno-associated viruses expressing short hairpin RNAs caused NCoR1 accumulation, inactivated PPARα, downregulated the expression of fatty acid oxidation-related genes and significantly increased liver triglyceride levels.
CONCLUSIONS
Our results elucidated a novel PPARα regulatory mechanism involving CMA-mediated NCoR1 degradation during aging. These findings demonstrate that CMA dysregulation is crucial for the progression of aging-related fatty liver diseases.
Topics: Animals; Mice; Chaperone-Mediated Autophagy; Autophagy; PPAR alpha; Aging; Liver; Lipid Metabolism; Fatty Acids
PubMed: 37524243
DOI: 10.1016/j.molmet.2023.101784 -
Experimental & Molecular Medicine Nov 2022The vitamin-C-synthesizing enzyme senescent marker protein 30 (SMP30) is a cold resistance gene in Drosophila, and vitamin C concentration increases in brown adipose...
The vitamin-C-synthesizing enzyme senescent marker protein 30 (SMP30) is a cold resistance gene in Drosophila, and vitamin C concentration increases in brown adipose tissue post-cold exposure. However, the roles of SMP30 in thermogenesis are unknown. Here, we tested the molecular mechanism of thermogenesis using wild-type (WT) and vitamin C-deficient SMP30-knockout (KO) mice. SMP30-KO mice gained more weight than WT mice without a change in food intake in response to short-term high-fat diet feeding. Indirect calorimetry and cold-challenge experiments indicated that energy expenditure is lower in SMP30-KO mice, which is associated with decreased thermogenesis in adipose tissues. Therefore, SMP30-KO mice do not lose weight during cold exposure, whereas WT mice lose weight markedly. Mechanistically, the levels of serum FGF21 were notably lower in SMP30-KO mice, and vitamin C supplementation in SMP30-KO mice recovered FGF21 expression and thermogenesis, with a marked reduction in body weight during cold exposure. Further experiments revealed that vitamin C activates PPARα to upregulate FGF21. Our findings demonstrate that SMP30-mediated synthesis of vitamin C activates the PPARα/FGF21 axis, contributing to the maintenance of thermogenesis in mice.
Topics: Animals; Mice; Adipose Tissue, Brown; Ascorbic Acid; Calcium-Binding Proteins; Intracellular Signaling Peptides and Proteins; Liver; Mice, Inbred C57BL; Mice, Knockout; PPAR alpha; Thermogenesis; Vitamins
PubMed: 36434042
DOI: 10.1038/s12276-022-00888-9 -
Free Radical Biology & Medicine Nov 2023Podocyte injury is a hallmark of glomerular disease and one of the leading causes of chronic kidney disease (CKD). Peroxisome proliferator-activated receptor α (PPARα)...
Podocyte injury is a hallmark of glomerular disease and one of the leading causes of chronic kidney disease (CKD). Peroxisome proliferator-activated receptor α (PPARα) plays a key role in podocyte fatty acid oxidation (FAO). However, the underlying regulatory mechanisms remain unresolved. Trim63 is an E3 ubiquitin ligase that has been shown to inhibit PPARα activity; however, its role in fatty acid metabolism in the kidney has not been elucidated to date. In this study, we investigated the effects of overexpression and knockdown of Trim63 in Adriamycin (ADR)-induced nephropathy and diabetic nephropathy models and a podocyte cell line. In both rodents and human patients with proteinuric CKD, Trim63 was upregulated, particularly in the podocytes of injured glomeruli. In the ADR-induced nephropathy model, ectopic Trim63 application aggravated FAO deficiency and mitochondrial dysfunction and triggered intense lipid deposition, podocyte injury, and proteinuria. Notably, Trim63 inhibition alleviated FAO deficiency and mitochondrial dysfunction, and markedly restored podocyte injury and renal fibrosis in ADR-induced and diabetic nephropathy (DN) models. Additionally, Trim63 was observed to mediate PPARα ubiquitination and degradation, leading to podocyte injury. We demonstrate the pathological role of Trim63, which was previously unrecognized in kidney tissue, in FAO deficiency and podocyte injury. Targeting Trim63 may represent a viable therapeutic strategy for podocyte injury and proteinuria.
Topics: Humans; Podocytes; PPAR alpha; Diabetic Nephropathies; Ubiquitin-Protein Ligases; Proteinuria; Doxorubicin; Renal Insufficiency, Chronic; Fatty Acids
PubMed: 37793501
DOI: 10.1016/j.freeradbiomed.2023.09.039