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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 2023The view that bone and energy metabolism are integrated by common regulatory mechanisms is broadly accepted and supported by multiple strands of evidence. This includes...
INTRODUCTION
The view that bone and energy metabolism are integrated by common regulatory mechanisms is broadly accepted and supported by multiple strands of evidence. This includes the well-characterized role of the PPARγ nuclear receptor, which is a common denominator in energy metabolism and bone metabolism. Little is known, however, about the role of PPARα nuclear receptor, a major regulator of lipid metabolism in other organs, in bone.
METHODS
A side-by-side comparative study of 5-15 mo old mice with global PPARα deficiency (α) and mice with osteocyte-specific PPARα deficiency (αOT) in order to parse out the various activities of PPARα in the skeleton that are of local and systemic significance. This study included transcriptome analysis of PPARα-deficient osteocytes, and analyses of bone mass and bone microarchitecture, systemic energy metabolism with indirect calorimetry, and differentiation potential of hematopoietic and mesenchymal bone cell progenitors. These analyses were paired with studies of either intact or silenced for PPARα MLO-A5 cells to determine PPARα role in osteocyte bioenergetics.
RESULTS
In osteocytes, PPARα controls large number of transcripts coding for signaling and secreted proteins which may regulate bone microenvironment and peripheral fat metabolism. In addition, PPARα in osteocytes controls their bioenergetics and mitochondrial response to stress, which constitutes up to 40% of total PPARα contribution to the global energy metabolism. Similarly to α mice, the metabolic phenotype of αOT mice (both males and females) is age-dependent. In younger mice, osteocyte metabolism contributes positively to global energetics, however, with aging the high-energy phenotype reverts to a low-energy phenotype and obesity develops, suggesting a longitudinal negative effect of impaired lipid metabolism and mitochondrial dysfunction in osteocytes deficient in PPARα. However, bone phenotype was not affected in αOT mice except in the form of an increased volume of marrow adipose tissue in males. In contrast, global PPARα deficiency in α mice led to enlarged bone diameter with a proportional increase in number of trabeculae and enlarged marrow cavities; it also altered differentiation of hematopoietic and mesenchymal marrow cells toward osteoclast, osteoblast and adipocyte lineages, respectively.
DISCUSSION
PPARα role in bone is multileveled and complex. In osteocytes, PPARα controls the bioenergetics of these cells, which significantly contributes to systemic energy metabolism and their endocrine/paracrine function in controlling marrow adiposity and peripheral fat metabolism.
Topics: Osteocytes; PPAR alpha; Bone and Bones; Energy Metabolism; Animals; Mice; Cells, Cultured; Male; Female; Signal Transduction; Mice, Knockout; Hematopoietic Stem Cells; Cell Differentiation; Age Factors; Gene Expression Profiling
PubMed: 37181042
DOI: 10.3389/fendo.2023.1145467 -
Journal of Ethnopharmacology May 2024Nonalcoholic steatohepatitis (NASH) is a prominent cause of liver-related death that poses a threat to global health and is characterized by severe hepatic steatosis,...
BACKGROUND
Nonalcoholic steatohepatitis (NASH) is a prominent cause of liver-related death that poses a threat to global health and is characterized by severe hepatic steatosis, lobular inflammation, and ballooning degeneration. To date, no Food and Drug Administration-approved medicine is commercially available. The Chaihu Guizhi Ganjiang Decoction (CGGD) shows potential curative effects on regulation of blood lipids and blood glucose, mitigation of organism inflammation, and amelioration of hepatic function. However, the overall regulatory mechanisms underlying its effects on NASH remain unclear.
PURPOSE
This study aimed to investigate the efficiency of CGGD on methionine- and choline-deficient (MCD)-induced NASH and unravel its underlying mechanisms.
METHODS
A NASH model of SD rats was established using an MCD diet for 8 weeks, and the efficacy of CGGD was evaluated based on hepatic lipid accumulation, inflammatory response, and fibrosis. The effects of CGGD on the intestinal barrier, metabolic profile, and differentially expressed genes (DEGs) profile were analyzed by integrating gut microbiota, metabolomics, and transcriptome sequencing to elucidate its mechanisms of action.
RESULTS
In MCD-induced NASH rats, pathological staining demonstrated that CGGD alleviated lipid accumulation, inflammatory cell infiltration, and fibrosis in the hepatic tissue. After CGGD administration, liver index, liver weight, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) contents, liver triglycerides (TG), and free fatty acids (FFAs) were decreased, meanwhile, it down-regulated the level of proinflammatory mediators (TNF-α, IL-6, IL-1β, MCP-1), and up-regulated the level of anti-inflammatory factors (IL-4, IL-10), and the expression of liver fibrosis markers TGFβ, Acta2, Col1a1 and Col1a2 were weakened. Mechanistically, CGGD treatment altered the diversity of intestinal flora, as evidenced by the depletion of Allobaculum, Blautia, norank_f_Erysipelotrichaceae, and enrichment of the probiotic genera Roseburia, Lactobacillus, Lachnoclostridium, etc. The colonic histopathological results indicated that the gut barrier damage recovered in the CGGD treatment group, and the expression levels of colonic short-chain fatty acids (SCFAs)-specific receptors FFAR2, FFAR3, and tight junction (TJs) proteins ZO-1, Occludin, Claudin-1 were increased compared with those in the model group. Further metabolomic and transcriptomic analyses suggested that CGGD mitigated the lipotoxicity caused by glycerophospholipid and eicosanoid metabolism disorders by decreasing the levels of PLA2G4A, LPCAT1, COX2, and LOX5. In addition, CGGD could activate the inhibitory lipotoxic transcription factor PPARα, regulate the proteins of FABP1, APOC2, APOA2, and LPL to promote fatty acid catabolism, and suppress the TLR4/MyD88/NFκB pathway to attenuate NASH.
CONCLUSION
Our study demonstrated that CGGD improved steatosis, inflammation, and fibrosis on NASH through enhancing intestinal barrier integrity and alleviating PPARα mediated lipotoxicity, which makes it an attractive candidate for potential new strategies for NASH prevention and treatment.
Topics: Rats; Animals; Mice; Non-alcoholic Fatty Liver Disease; PPAR alpha; Rats, Sprague-Dawley; Liver; Liver Cirrhosis; Inflammation; Lipids; Methionine; Mice, Inbred C57BL; Drugs, Chinese Herbal
PubMed: 38310988
DOI: 10.1016/j.jep.2024.117841 -
Biochemical and Biophysical Research... Jun 2024Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder among women of reproductive age, is characterized by disturbances in hormone levels and ovarian...
BACKGROUND
Polycystic ovary syndrome (PCOS), a prevalent endocrine disorder among women of reproductive age, is characterized by disturbances in hormone levels and ovarian dysfunction. Ferroptosis, a unique form of regulated cell death characterized by iron-dependent lipid peroxidation. Emerging evidence indicates that ferroptosis may have a significant role in the pathogenesis of PCOS, highlighting the importance of studying this mechanism to better understand the disorder and potentially develop novel therapeutic interventions.
METHODS
To create an in vivo PCOS model, mice were injected with dehydroepiandrosterone (DHEA) and the success of the model was confirmed through further assessments. Ferroptosis levels were evaluated through detecting ferroptosis-related indicators. Ferroptosis-related genes were found through bioinformatic analysis and identified by experiments. An in vitro PCOS model was also established using DHEA treated KGN cells. The molecular binding relationship was confirmed using a chromatin immunoprecipitation (ChIP) assay.
RESULTS
In PCOS model, various ferroptosis-related indicators such as MDA, Fe, and lipid ROS showed an increase, while GSH, GPX4, and TFR1 exhibited a decrease. These findings indicate an elevated level of ferroptosis in the PCOS model. The ferroptosis-related gene FADS2 was identified and validated. FADS2 and PPAR-α were shown to be highly expressed in ovarian tissue and primary granulosa cells (GCs) of PCOS mice. Furthermore, the overexpression of both FADS2 and PPAR-α in KGN cells effectively suppressed the DHEA-induced increase in ferroptosis-related indicators (MDA, Fe, and lipid ROS) and the decrease in GSH, GPX4, and TFR1 levels. The ferroptosis agonist erastin reversed the suppressive effect, suggesting the involvement of ferroptosis in this process. Additionally, the FADS2 inhibitor SC26196 was found to inhibit the effect of PPAR-α on ferroptosis. Moreover, the binding of PPAR-α to the FADS2 promoter region was predicted and confirmed. This indicates the regulatory relationship between PPAR-α and FADS2 in the context of ferroptosis.
CONCLUSIONS
Our study indicates that PPAR-α may have an inhibitory effect on DHEA-induced ferroptosis in GCs by enhancing the expression of FADS2. This discovery provides valuable insights into the pathophysiology and potential therapeutic targets for PCOS.
Topics: Ferroptosis; Female; Animals; Granulosa Cells; Dehydroepiandrosterone; Mice; Up-Regulation; Polycystic Ovary Syndrome; PPAR alpha; Humans; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 38678785
DOI: 10.1016/j.bbrc.2024.150005 -
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 -
Molecular and Cellular Endocrinology May 2024To evaluate the effects of PPARα and PPARγ activation (alone or in combination) on the gut-liver axis, emphasizing the integrity of the intestinal barrier and hepatic...
AIM
To evaluate the effects of PPARα and PPARγ activation (alone or in combination) on the gut-liver axis, emphasizing the integrity of the intestinal barrier and hepatic steatosis in mice fed a high saturated fat diet.
METHODS
Male C57BL/6J were fed a control diet (C) or a high-fat diet (HF) for ten weeks. Then, a four-week treatment started: HF-α (WY14643), HF-γ (low-dose pioglitazone), and HF-αγ (combination).
RESULTS
The HF caused overweight, insulin resistance, impaired gut-liver axis, and marked hepatic steatosis. Treatments reduced body mass, improved glucose homeostasis, and restored the gut microbiota diversity and intestinal barrier gene expression. Treatments also lowered the plasma lipopolysaccharide concentrations and favored beta-oxidation genes, reducing macrophage infiltration and steatosis in the liver.
CONCLUSION
Treatment with PPAR agonists modulated the gut microbiota and rescued the integrity of the intestinal barrier, alleviating hepatic steatosis. These results show that these agonists can contribute to metabolic-associated fatty liver disease treatment.
Topics: Male; Animals; Mice; Diet, High-Fat; PPAR alpha; Obesity; Mice, Inbred C57BL; Liver; Non-alcoholic Fatty Liver Disease
PubMed: 38373652
DOI: 10.1016/j.mce.2024.112177 -
ELife Jul 2023Flavin adenine dinucleotide (FAD) interacts with flavoproteins to mediate oxidation-reduction reactions required for cellular energy demands. Not surprisingly, mutations...
Flavin adenine dinucleotide (FAD) interacts with flavoproteins to mediate oxidation-reduction reactions required for cellular energy demands. Not surprisingly, mutations that alter FAD binding to flavoproteins cause rare inborn errors of metabolism (IEMs) that disrupt liver function and render fasting intolerance, hepatic steatosis, and lipodystrophy. In our study, depleting FAD pools in mice with a vitamin B2-deficient diet (B2D) caused phenotypes associated with organic acidemias and other IEMs, including reduced body weight, hypoglycemia, and fatty liver disease. Integrated discovery approaches revealed B2D tempered fasting activation of target genes for the nuclear receptor PPARα, including those required for gluconeogenesis. We also found PPARα knockdown in the liver recapitulated B2D effects on glucose excursion and fatty liver disease in mice. Finally, treatment with the PPARα agonist fenofibrate activated the integrated stress response and refilled amino acid substrates to rescue fasting glucose availability and overcome B2D phenotypes. These findings identify metabolic responses to FAD availability and nominate strategies for the management of organic acidemias and other rare IEMs.
Topics: Mice; Animals; Glucose; PPAR alpha; Flavin-Adenine Dinucleotide; Fatty Acids; Liver; Fasting; Non-alcoholic Fatty Liver Disease; Oxidation-Reduction; Flavoproteins
PubMed: 37417957
DOI: 10.7554/eLife.84077 -
Proceedings of the National Academy of... Oct 2022Ketone bodies are energy-rich metabolites and signaling molecules whose production is mainly regulated by diet. Caloric restriction (CR) is a dietary intervention that...
Ketone bodies are energy-rich metabolites and signaling molecules whose production is mainly regulated by diet. Caloric restriction (CR) is a dietary intervention that improves metabolism and extends longevity across the taxa. We found that CR induced high-amplitude daily rhythms in blood ketone bodies (beta-hydroxybutyrate [βOHB]) that correlated with liver βOHB level. Time-restricted feeding, another periodic fasting-based diet, also led to rhythmic βOHB but with reduced amplitude. CR induced strong circadian rhythms in the expression of fatty acid oxidation and ketogenesis genes in the liver. The transcriptional factor peroxisome-proliferator-activated-receptor α (PPARα) and its transcriptional target hepatokine fibroblast growth factor 21 (FGF21) are primary regulators of ketogenesis. expression and the PPARα transcriptional network became highly rhythmic in the CR liver, which implicated the involvement of the circadian clock. Mechanistically, the circadian clock proteins CLOCK, BMAL1, and cryptochromes (CRYs) interfered with PPARα transcriptional activity. Daily rhythms in the blood βOHB level and in the expression of PPARα target genes were significantly impaired in circadian clock-deficient mice. These data suggest that blood βOHB level is tightly controlled and that the circadian clock is a regulator of diet-induced ketogenesis.
Topics: 3-Hydroxybutyric Acid; ARNTL Transcription Factors; Animals; Circadian Clocks; Circadian Rhythm; Cryptochromes; Gene Regulatory Networks; Ketone Bodies; Liver; Mice; PPAR alpha
PubMed: 36161962
DOI: 10.1073/pnas.2205755119 -
Molecules (Basel, Switzerland) Feb 2020Recently, peroxisome proliferator-activated receptor (PPAR)-α and γ isoforms have been gaining consistent interest in neuropathology and treatment of neuropsychiatric... (Review)
Review
Recently, peroxisome proliferator-activated receptor (PPAR)-α and γ isoforms have been gaining consistent interest in neuropathology and treatment of neuropsychiatric disorders. Several studies have provided evidence that either the receptor expression or the levels of their endogenously-produced modulators are downregulated in several neurological and psychiatric disorders and in their respective animal models. Remarkably, administration of these endogenous or synthetic ligands improves mood and cognition, suggesting that PPARs may offer a significant pharmacological target to improve several neuropathologies. Furthermore, various neurological and psychiatric disorders reflect sustained levels of systemic inflammation. Hence, the strategy of targeting PPARs for their anti-inflammatory role to improve these disorders is attracting attention. Traditionally, classical antidepressants fail to be effective, specifically in patients with inflammation. Non-steroidal anti-inflammatory drugs exert potent antidepressant effects by acting along with PPARs, thereby strongly substantiating the involvement of these receptors in the mechanisms that lead to development of several neuropathologies. We reviewed running findings in support of a role for PPARs in the treatment of neurological diseases, including Alzheimer's disease or psychiatric disorders, such as major depression. We discuss the opportunity of targeting PPARs as a future pharmacological approach to decrease neuropsychiatric symptoms at the same time that PPAR ligands resolve neuroinflammatory processes.
Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents; Autism Spectrum Disorder; Brain; Depressive Disorder, Major; Humans; Inflammation; Ligands; PPAR alpha; PPAR gamma; Schizophrenia
PubMed: 32120979
DOI: 10.3390/molecules25051062