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Cells Oct 2020Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that function as ligand-activated transcription factors. They exist in three isoforms: PPARα,...
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that function as ligand-activated transcription factors. They exist in three isoforms: PPARα, PPARβ/δ, and PPARγ. For all PPARs, lipids are endogenous ligands, linking them directly to metabolism. PPARs form heterodimers with retinoic X receptors, and upon ligand binding, they modulate the gene expression of downstream target genes, depending on the presence of co-repressors or co-activators. This results in a complex, cell type-specific regulation of proliferation, differentiation, and cell survival. PPARs are linked to metabolic disorders and are interesting pharmaceutical targets. PPARα and PPARγ agonists are already in clinical use for the treatment of hyperlipidemia and type 2 diabetes, respectively. More recently, PPARβ/δ activation came into focus as an interesting novel approach for the treatment of metabolic syndrome and associated cardiovascular diseases; however, this has been limited due to the highly controversial function of PPARβ/δ in cancer. This Special Issue of brings together the most recent advances in understanding the various aspects of the action of PPARs, and it provides new insights into our understanding of PPARs, implying also the latest therapeutic perspectives for the utility of PPAR modulation in different disease settings.
Topics: Adipocytes; Animals; Disease; Humans; Ligands; Neovascularization, Physiologic; Peroxisome Proliferator-Activated Receptors; Signal Transduction
PubMed: 33126411
DOI: 10.3390/cells9112367 -
Hepatology (Baltimore, Md.) Jan 2022Peroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy...
BACKGROUND AND AIMS
Peroxisome proliferator-activated receptor α (PPARα, NR1C1) is a ligand-activated nuclear receptor involved in the regulation of lipid catabolism and energy homeostasis. PPARα activation induces hepatomegaly and plays an important role in liver regeneration, but the underlying mechanisms remain unclear.
APPROACH AND RESULTS
In this study, the effect of PPARα activation on liver enlargement and regeneration was investigated in several strains of genetically modified mice. PPARα activation by the specific agonist WY-14643 significantly induced hepatomegaly and accelerated liver regeneration after 70% partial hepatectomy (PHx) in wild-type mice and Ppara mice, while these effects were abolished in hepatocyte-specific Ppara-deficient (Ppara ) mice. Moreover, PPARα activation promoted hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area. Mechanistically, PPARα activation regulated expression of yes-associated protein (YAP) and its downstream targets (connective tissue growth factor, cysteine-rich angiogenic inducer 61, and ankyrin repeat domain 1) as well as proliferation-related proteins (cyclins A1, D1, and E1). Binding of YAP with the PPARα E domain was critical for the interaction between YAP and PPARα. PPARα activation further induced nuclear translocation of YAP. Disruption of the YAP-transcriptional enhancer factor domain family member (TEAD) association significantly suppressed PPARα-induced hepatomegaly and hepatocyte enlargement and proliferation. In addition, PPARα failed to induce hepatomegaly in adeno-associated virus-Yap short hairpin RNA-treated mice and liver-specific Yap-deficient mice. Blockade of YAP signaling abolished PPARα-induced hepatocyte hypertrophy around the central vein area and hepatocyte proliferation around the portal vein area.
CONCLUSIONS
This study revealed a function of PPARα in regulating liver size and liver regeneration through activation of the YAP-TEAD signaling pathway. These findings have implications for understanding the physiological functions of PPARα and suggest its potential for manipulation of liver size and liver regeneration.
Topics: Animals; Cell Proliferation; Disease Models, Animal; Gene Expression Regulation; Gene Knockdown Techniques; Hepatectomy; Hepatocytes; Hepatomegaly; Humans; Liver; Liver Regeneration; Male; Mice; Mice, Transgenic; PPAR alpha; Pyrimidines; Signal Transduction; TEA Domain Transcription Factors; YAP-Signaling Proteins
PubMed: 34387904
DOI: 10.1002/hep.32105 -
Biomedicine & Pharmacotherapy =... Jul 2021Doxorubicin (Dox) is a secondary metabolite of the mutated strain of Streptomyces peucetius var. Caesius and belongs to the anthracyclines family. The anti-cancer... (Review)
Review
Doxorubicin (Dox) is a secondary metabolite of the mutated strain of Streptomyces peucetius var. Caesius and belongs to the anthracyclines family. The anti-cancer activity of Dox is mainly exerted through the DNA intercalation and inhibiting topoisomerase II enzyme in fast-proliferating tumors. However, Dox causes cumulative and dose-dependent cardiotoxicity, which results in increased risks of mortality among cancer patients and thus limiting its wide clinical applications. There are several mechanisms has been proposed for doxorubicin-induced cardiotoxicity and oxidative stress, free radical generation and apoptosis are most widely reported. Apart from this, other mechanisms are also involved in Dox-induced cardiotoxicity such as impaired mitochondrial function, a perturbation in iron regulatory protein, disruption of Ca homeostasis, autophagy, the release of nitric oxide and inflammatory mediators and altered gene and protein expression that involved apoptosis. Dox also causes downregulation of DNA methyltransferase 1 (DNMT1) enzyme activity which leads to a reduction in the DNA methylation process. This hypomethylation causes dysregulation in the mitochondrial genes like peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1-alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM) unit in the heart. Apart from DNA methylation, Dox treatment also alters the micro RNAs levels and histone deacetylase (HDAC) activity. Therefore, in the current review, we have provided a detailed update on the current understanding of the pathological mechanisms behind the well-known Dox-induced cardiotoxicity. Further, we have provided some of the most plausible pharmacological strategies which have been tested against Dox-induced cardiotoxicity.
Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Cardiotoxicity; Doxorubicin; Humans; Mitochondria, Heart; Oxidative Stress
PubMed: 34243633
DOI: 10.1016/j.biopha.2021.111708 -
Molecular Cell Dec 2019Hypoxia, which occurs during tumor growth, triggers complex adaptive responses in which peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α)...
Hypoxia, which occurs during tumor growth, triggers complex adaptive responses in which peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) plays a critical role in mitochondrial biogenesis and oxidative metabolism. However, how PGC-1α is regulated in response to oxygen availability remains unclear. We demonstrated that lysine demethylase 3A (KDM3A) binds to PGC-1α and demethylates monomethylated lysine (K) 224 of PGC-1α under normoxic conditions. Hypoxic stimulation inhibits KDM3A, which has a high K of oxygen for its activity, and enhances PGC-1α K224 monomethylation. This modification decreases PGC-1α's activity required for NRF1- and NRF2-dependent transcriptional regulation of TFAM, TFB1M, and TFB2M, resulting in reduced mitochondrial biogenesis. Expression of PGC-1α K224R mutant significantly increases mitochondrial biogenesis, reactive oxygen species (ROS) production, and tumor cell apoptosis under hypoxia and inhibits brain tumor growth in mice. This study revealed that PGC-1α monomethylation, which is dependent on oxygen availability-regulated KDM3A, plays a critical role in the regulation of mitochondrial biogenesis.
Topics: Animals; Apoptosis; Brain Neoplasms; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; HEK293 Cells; HeLa Cells; Hep G2 Cells; Humans; Jumonji Domain-Containing Histone Demethylases; Methylation; Mice, Inbred BALB C; Mice, Nude; Mitochondria; Organelle Biogenesis; Oxygen; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Protein Processing, Post-Translational; Reactive Oxygen Species; Signal Transduction; Tumor Burden; Tumor Hypoxia; Tumor Microenvironment
PubMed: 31629659
DOI: 10.1016/j.molcel.2019.09.019 -
International Journal of Molecular... Oct 2019Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development,... (Review)
Review
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner. Pemafibrate, due to its high selectivity, is likely to replace other PPARα agonists for dyslipidemia and cardiovascular diseases. PPARγ agonist pioglitazone showed tremendous promises in many non-metabolic disorders like chronic kidney disease, depression, inflammation, and autoimmune diseases. The clinical niche of PPARβ/δ agonists is less well-explored. Interestingly, dual- or pan-PPAR agonists, namely chiglitazar, saroglitazar, elafibranor, and lanifibranor, are gaining momentum with their optimistic outcomes in many diseases including type 2 diabetes, dyslipidemia, non-alcoholic fatty liver disease, and primary biliary cholangitis. Notably, the preclinical and clinical development for PPAR antagonists remains unacceptably deficient. We anticipate the future design of better PPAR modulators with minimal off-target effects, high selectivity, superior bioavailability, and pharmacokinetics. This will open new possibilities for PPAR ligands in medicine.
Topics: Animals; Biological Availability; Cell Proliferation; Clinical Trials as Topic; Drug Discovery; Energy Metabolism; Gene Expression Regulation; Humans; Ligands; Peroxisome Proliferator-Activated Receptors
PubMed: 31614690
DOI: 10.3390/ijms20205055 -
Cell Reports Jun 2021Obesity is an established risk factor for cancer in many tissues. In the mammalian intestine, a pro-obesity high-fat diet (HFD) promotes regeneration and tumorigenesis...
Obesity is an established risk factor for cancer in many tissues. In the mammalian intestine, a pro-obesity high-fat diet (HFD) promotes regeneration and tumorigenesis by enhancing intestinal stem cell (ISC) numbers, proliferation, and function. Although PPAR (peroxisome proliferator-activated receptor) nuclear receptor activity has been proposed to facilitate these effects, their exact role is unclear. Here we find that, in loss-of-function in vivo models, PPARα and PPARδ contribute to the HFD response in ISCs. Mechanistically, both PPARs do so by robustly inducing a downstream fatty acid oxidation (FAO) metabolic program. Pharmacologic and genetic disruption of CPT1A (the rate-controlling enzyme of mitochondrial FAO) blunts the HFD phenotype in ISCs. Furthermore, inhibition of CPT1A dampens the pro-tumorigenic consequences of a HFD on early tumor incidence and progression. These findings demonstrate that inhibition of a HFD-activated FAO program creates a therapeutic opportunity to counter the effects of a HFD on ISCs and intestinal tumorigenesis.
Topics: Animals; Carcinogenesis; Diet, High-Fat; Fatty Acids; Humans; Intestines; Mice; Obesity; Oxidation-Reduction; PPAR alpha; Stem Cells
PubMed: 34107251
DOI: 10.1016/j.celrep.2021.109212 -
Theranostics 2020: Myocardial vulnerability to ischemia/reperfusion (I/R) injury is strictly regulated by energy substrate metabolism. Branched chain amino acids (BCAA), consisting of...
: Myocardial vulnerability to ischemia/reperfusion (I/R) injury is strictly regulated by energy substrate metabolism. Branched chain amino acids (BCAA), consisting of valine, leucine and isoleucine, are a group of essential amino acids that are highly oxidized in the heart. Elevated levels of BCAA have been implicated in the development of cardiovascular diseases; however, the role of BCAA in I/R process is not fully understood. The present study aims to determine how BCAA influence myocardial energy substrate metabolism and to further clarify the pathophysiological significance during cardiac I/R injury. : Parameters of glucose and fatty acid metabolism were measured by seahorse metabolic flux analyzer in adult mouse cardiac myocytes with or without BCAA incubation Chronic accumulation of BCAA was induced in mice receiving oral BCAA administration. A genetic mouse model with defective BCAA catabolism was also utilized. Mice were subjected to MI/R and the injury was assessed extensively at the whole-heart, cardiomyocyte, and molecular levels. : We confirmed that chronic accumulation of BCAA enhanced glycolysis and fatty acid oxidation (FAO) but suppressed glucose oxidation in adult mouse ventricular cardiomyocytes. Oral gavage of BCAA enhanced FAO in cardiac tissues, exacerbated lipid peroxidation toxicity and worsened myocardial vulnerability to I/R injury. Etomoxir, a specific inhibitor of FAO, rescued the deleterious effects of BCAA on I/R injury. Mechanistically, valine, leucine and their corresponding branched chain α-keto acid (BCKA) derivatives, but not isoleucine and its BCKA derivative, transcriptionally upregulated peroxisome proliferation-activated receptor alpha (PPAR-α). BCAA/BCKA induced PPAR-α upregulation through the general control nonderepresible-2 (GCN2)/ activating transcription factor-6 (ATF6) pathway. Finally, in a genetic mouse model with BCAA catabolic defects, chronic accumulation of BCAA increased FAO in myocardial tissues and sensitized the heart to I/R injury, which could be reversed by adenovirus-mediated PPAR-α silencing. : We identify BCAA as an important nutrition regulator of myocardial fatty acid metabolism through transcriptional upregulation of PPAR-α. Chronic accumulation of BCAA, caused by either dietary or genetic factors, renders the heart vulnerable to I/R injury via exacerbating lipid peroxidation toxicity. These data support the notion that BCAA lowering methods might be potentially effective cardioprotective strategies, especially among patients with diseases characterized by elevated levels of BCAA, such as obesity and diabetes.
Topics: Activating Transcription Factor 6; Amino Acids, Branched-Chain; Animals; Cells, Cultured; Disease Models, Animal; Energy Metabolism; Fatty Acids; Glucose; Mice; Mice, Knockout; Myocardial Reperfusion Injury; Myocytes, Cardiac; Oxidation-Reduction; PPAR alpha; Protein Serine-Threonine Kinases
PubMed: 32373236
DOI: 10.7150/thno.44836 -
Science Advances May 2023Proliferating cells rely on acetyl-CoA to support membrane biogenesis and acetylation. Several organelle-specific pathways are available for provision of acetyl-CoA as...
Proliferating cells rely on acetyl-CoA to support membrane biogenesis and acetylation. Several organelle-specific pathways are available for provision of acetyl-CoA as nutrient availability fluctuates, so understanding how cells maintain acetyl-CoA homeostasis under such stresses is critically important. To this end, we applied C isotope tracing cell lines deficient in these mitochondrial [ATP-citrate lyase (ACLY)]-, cytosolic [acetyl-CoA synthetase (ACSS2)]-, and peroxisomal [peroxisomal biogenesis factor 5 (PEX5)]-dependent pathways. ACLY knockout in multiple cell lines reduced fatty acid synthesis and increased reliance on extracellular lipids or acetate. Knockout of both ACLY and ACSS2 (DKO) severely stunted but did not entirely block proliferation, suggesting that alternate pathways can support acetyl-CoA homeostasis. Metabolic tracing and PEX5 knockout studies link peroxisomal oxidation of exogenous lipids as a major source of acetyl-CoA for lipogenesis and histone acetylation in cells lacking ACLY, highlighting a role for inter-organelle cross-talk in supporting cell survival in response to nutrient fluctuations.
Topics: Lipogenesis; Acetyl Coenzyme A; Acetates; ATP Citrate (pro-S)-Lyase; Mitochondria; Homeostasis; Stress, Physiological
PubMed: 37134162
DOI: 10.1126/sciadv.adf0138 -
Nature Metabolism Sep 2021Excess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance, which causes obesity and an increased risk of type 2 diabetes...
Excess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance, which causes obesity and an increased risk of type 2 diabetes and colorectal cancer. This functional maladaptation is thought to emerge at the level of the intestinal stem cells (ISCs). However, it is not clear how an obesogenic diet affects ISC identity and fate. Here we show that an obesogenic diet induces ISC and progenitor hyperproliferation, enhances ISC differentiation and cell turnover and changes the regional identities of ISCs and enterocytes in mice. Single-cell resolution of the enteroendocrine lineage reveals an increase in progenitors and peptidergic enteroendocrine cell types and a decrease in serotonergic enteroendocrine cell types. Mechanistically, we link increased fatty acid synthesis, Ppar signaling and the Insr-Igf1r-Akt pathway to mucosal changes. This study describes molecular mechanisms of diet-induced intestinal maladaptation that promote obesity and therefore underlie the pathogenesis of the metabolic syndrome and associated complications.
Topics: Animals; Cell Lineage; Cell Proliferation; Diet, High-Fat; Fatty Acids; Intestines; Mice; Obesity; Peroxisome Proliferator-Activated Receptors; Prediabetic State; Signal Transduction; Stem Cells
PubMed: 34552271
DOI: 10.1038/s42255-021-00458-9 -
Frontiers in Physiology 2022Organelles within the cell are highly dynamic entities, requiring dramatic morphological changes to support their function and maintenance. As a result, organelle... (Review)
Review
Organelles within the cell are highly dynamic entities, requiring dramatic morphological changes to support their function and maintenance. As a result, organelle membranes are also highly dynamic, adapting to a range of topologies as the organelle changes shape. In particular, peroxisomes-small, ubiquitous organelles involved in lipid metabolism and reactive oxygen species homeostasis-display a striking plasticity, for example, during the growth and division process by which they proliferate. During this process, the membrane of an existing peroxisome elongates to form a tubule, which then constricts and ultimately undergoes scission to generate new peroxisomes. Dysfunction of this plasticity leads to diseases with developmental and neurological phenotypes, highlighting the importance of peroxisome dynamics for healthy cell function. What controls the dynamics of peroxisomal membranes, and how this influences the dynamics of the peroxisomes themselves, is just beginning to be understood. In this review, we consider how the composition, biophysical properties, and protein-lipid interactions of peroxisomal membranes impacts on their dynamics, and in turn on the biogenesis and function of peroxisomes. In particular, we focus on the effect of the peroxin PEX11 on the peroxisome membrane, and its function as a major regulator of growth and division. Understanding the roles and regulation of peroxisomal membrane dynamics necessitates a multidisciplinary approach, encompassing knowledge across a range of model species and a number of fields including lipid biochemistry, biophysics and computational biology. Here, we present an integrated overview of our current understanding of the determinants of peroxisome membrane dynamics, and reflect on the outstanding questions still remaining to be solved.
PubMed: 35185625
DOI: 10.3389/fphys.2022.834411