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Journal of Alzheimer's Disease : JAD 2019Mounting evidence has identified that impaired amyloid-β (Aβ) clearance might contribute to Alzheimer's disease (AD) pathology. The lysosome-autophagy network plays an... (Review)
Review
Mounting evidence has identified that impaired amyloid-β (Aβ) clearance might contribute to Alzheimer's disease (AD) pathology. The lysosome-autophagy network plays an important role in protein homeostasis and cell health by removing abnormal protein aggregates via intracellular degradation. Therefore, stimulation of cellular degradative machinery for efficient removal of Aβ has emerged as a growing field in AD research. However, mechanisms controlling such pathways and drugs to promote such mechanisms are poorly understood. Aspirin is a widely used drug throughout the world and recent studies have identified a new function of this drug. At low doses, aspirin stimulates lysosomal biogenesis and autophagy to clear amyloid plaques in an animal model of AD. This review delineates such functions of aspirin and analyzes underlying mechanisms that involve peroxisome proliferator-activated receptor alpha (PPARα)-mediated transcription of transcription factor EB (TFEB), the master regulator of lysosomal biogenesis.
Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Humans; PPAR alpha; Plaque, Amyloid; Protein Binding; Protein Structure, Secondary
PubMed: 31424405
DOI: 10.3233/JAD-190586 -
Mini Reviews in Medicinal Chemistry 2019Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors which belong to the ligand-activated nuclear receptor superfamily. They are ubiquitously... (Review)
Review
Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors which belong to the ligand-activated nuclear receptor superfamily. They are ubiquitously expressed throughout the body. So far, three major subtypes have been identified, PPARα, PPARβ/δ and PPARγ. They are crucial for lipid and glucose metabolism and are also involved in the regulation of several types of tumors, inflammation, cardiovascular diseases and infertility. The importance of these transcription factors in physiology and pathophysiology has been largely investigated. Synthetic PPAR ligands are widely used in the treatment of dyslipidemia (e.g. fibrates - PPARα activators) or in diabetes mellitus (e.g. thiazolidinediones - PPARγ agonists) while a new generation of dual agonists reveals hypolipemic, hypotensive, antiatherogenic, anti-inflammatory and anticoagulant action. Many natural ligands, including polyphenolic compounds, influence the expression of these receptors. They have several health-promoting properties, including antioxidant, anti-inflammatory, and antineoplastic activities. Resveratrol, a stilbene polyphenol, is a biological active modulator of several signaling proteins, including PPARs. Given the enormous pharmacological potential of resveratrol, stilbene-based medicinal chemistry had a rapid increase covering various areas of research. The present review discusses ligands of PPARs that contain stilbene scaffold and summarises the different types of compounds on the basis of chemical structure.
Topics: Diabetes Mellitus; Dyslipidemias; Humans; Ligands; PPAR alpha; PPAR gamma; Stilbenes; Thiazolidinediones
PubMed: 31161987
DOI: 10.2174/1389557519666190603085026 -
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 -
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 -
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 -
Medicinal Research Reviews Nov 2023The prevalence of cardiovascular disease (CVD) has been rising due to sedentary lifestyles and unhealthy dietary patterns. Peroxisome proliferator-activated receptor α... (Review)
Review
The prevalence of cardiovascular disease (CVD) has been rising due to sedentary lifestyles and unhealthy dietary patterns. Peroxisome proliferator-activated receptor α (PPARα) is a nuclear receptor regulating multiple biological processes, such as lipid metabolism and inflammatory response critical to cardiovascular homeostasis. Healthy endothelial cells (ECs) lining the lumen of blood vessels maintains vascular homeostasis, where endothelial dysfunction associated with increased oxidative stress and inflammation triggers the pathogenesis of CVD. PPARα activation decreases endothelial inflammation and senescence, contributing to improved vascular function and reduced risk of atherosclerosis. Phenotypic switch and inflammation of vascular smooth muscle cells (VSMCs) exacerbate vascular dysfunction and atherogenesis, in which PPARα activation improves VSMC homeostasis. Different immune cells participate in the progression of vascular inflammation and atherosclerosis. PPARα in immune cells plays a critical role in immunological events, such as monocyte/macrophage adhesion and infiltration, macrophage polarization, dendritic cell (DC) embedment, T cell activation, and B cell differentiation. Cardiomyocyte dysfunction, a major risk factor for heart failure, can also be alleviated by PPARα activation through maintaining cardiac mitochondrial stability and inhibiting cardiac lipid accumulation, oxidative stress, inflammation, and fibrosis. This review discusses the current understanding and future perspectives on the role of PPARα in the regulation of the cardiovascular system as well as the clinical application of PPARα ligands.
Topics: Humans; PPAR alpha; Endothelial Cells; Atherosclerosis; Inflammation; Cardiovascular Diseases; Cardiovascular System
PubMed: 37119045
DOI: 10.1002/med.21970 -
Trends in Pharmacological Sciences Jan 2024Peroxisome proliferator-activated receptors [PPARs; PPARα, PPARβ/δ (also known as PPARδ), and PPARγ] widely recognized for their important role in glucose/lipid... (Review)
Review
Peroxisome proliferator-activated receptors [PPARs; PPARα, PPARβ/δ (also known as PPARδ), and PPARγ] widely recognized for their important role in glucose/lipid homeostasis, have recently received significant attention due to their additional anti-inflammatory and neuroprotective effects. Several newly developed PPAR agonists have shown high selectivity for specific PPAR isoforms in vitro and in vivo, offering the potential to achieve desired therapeutic outcomes while reducing the risk of adverse effects. In this review, we discuss the latest preclinical and clinical studies of the activation of PPARs by synthetic, natural, and isoform-specific (full, partial, and dual) agonists for the treatment of neuroinflammatory diseases, including HIV-associated neurocognitive disorders (HAND), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and cerebral ischemia.
Topics: Humans; Peroxisome Proliferator-Activated Receptors; Neuroinflammatory Diseases; PPAR delta; PPAR-beta; PPAR alpha; PPAR gamma; Hypoglycemic Agents
PubMed: 38065777
DOI: 10.1016/j.tips.2023.11.004 -
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 -
International Journal of Molecular... Sep 2021Peroxisome proliferator-activated receptor α is a potent regulator of systemic and cellular metabolism and energy homeostasis, but it also suppresses various... (Review)
Review
Peroxisome proliferator-activated receptor α is a potent regulator of systemic and cellular metabolism and energy homeostasis, but it also suppresses various inflammatory reactions. In this review, we focus on its role in the regulation of innate immunity; in particular, we discuss the PPARα interplay with inflammatory transcription factor signaling, pattern-recognition receptor signaling, and the endocannabinoid system. We also present examples of the PPARα-specific immunomodulatory functions during parasitic, bacterial, and viral infections, as well as approach several issues associated with innate immunity processes, such as the production of reactive nitrogen and oxygen species, phagocytosis, and the effector functions of macrophages, innate lymphoid cells, and mast cells. The described phenomena encourage the application of endogenous and pharmacological PPARα agonists to alleviate the disorders of immunological background and the development of new solutions that engage PPARα activation or suppression.
Topics: Adaptive Immunity; Animals; Energy Metabolism; Homeostasis; Humans; Immunity, Innate; Inflammation; Macrophages; PPAR alpha; Signal Transduction
PubMed: 34638886
DOI: 10.3390/ijms221910545 -
Phytotherapy Research : PTR Nov 2023Cardiovascular diseases are currently the primary cause of mortality in the whole world. Growing evidence indicated that the disturbances in cardiac fatty acid... (Review)
Review
Cardiovascular diseases are currently the primary cause of mortality in the whole world. Growing evidence indicated that the disturbances in cardiac fatty acid metabolism are crucial contributors in the development of cardiovascular diseases. The abnormal cardiac fatty acid metabolism usually leads to energy deficit, oxidative stress, excessive apoptosis, and inflammation. Targeting fatty acid metabolism has been regarded as a novel approach to the treatment of cardiovascular diseases. However, there are currently no specific drugs that regulate fatty acid metabolism to treat cardiovascular diseases. Many traditional Chinese medicines have been widely used to treat cardiovascular diseases in clinics. And modern studies have shown that they exert a cardioprotective effect by regulating the expression of key proteins involved in fatty acid metabolism, such as peroxisome proliferator-activated receptor α and carnitine palmitoyl transferase 1. Hence, we systematically reviewed the relationship between fatty acid metabolism disorders and four types of cardiovascular diseases including heart failure, coronary artery disease, cardiac hypertrophy, and diabetic cardiomyopathy. In addition, 18 extracts and eight monomer components from traditional Chinese medicines showed cardioprotective effects by restoring cardiac fatty acid metabolism. This work aims to provide a reference for the finding of novel cardioprotective agents targeting fatty acid metabolism.
Topics: Humans; Cardiovascular Diseases; Heart; Medicine, Chinese Traditional; PPAR alpha; Fatty Acids; Energy Metabolism
PubMed: 37533230
DOI: 10.1002/ptr.7965