Roles of histone deacetylation and AMP kinase in regulation of cardiomyocyte PGC-1α gene expression in hypoxia

2013 ◽  
Vol 304 (11) ◽  
pp. C1064-C1072 ◽  
Author(s):  
Angela Ramjiawan ◽  
Rushita A. Bagchi ◽  
Alexandra Blant ◽  
Laura Albak ◽  
Maria A. Cavasin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Histone Deacetylation ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Rat Cardiomyocytes ◽  
Glucose Depletion ◽  
And Function ◽  
Amp Activated Protein Kinase

The transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a key determinant of cardiac metabolic function by regulating genes governing fatty acid oxidation and mitochondrial biogenesis. PGC-1α expression is reduced in many cardiac diseases, and gene deletion of PGC-1α results in impaired cardiomyocyte metabolism and function. Reduced fuel supply generally induces PGC-1α expression, but the specific role of oxygen deprivation is unclear, and the mechanisms governing PGC-1α gene expression in these situations are poorly understood. During hypoxia of primary rat cardiomyocytes up to 12 h, we found that PGC-1α expression was downregulated via a histone deacetylation-dependent mechanism. Conversely, extended hypoxia to 24 h concomitant with glucose depletion upregulated PGC-1α expression via an AMP-activated protein kinase (AMPK)-mediated mechanism. Our previous work demonstrated that estrogen-related receptor-α (ERRα) regulates PGC-1α expression, and we show here that overexpression of ERRα was sufficient to attenuate PGC-1α downregulation in hypoxia. We confirmed that chronic hypoxia downregulated cardiac PGC-1α expression in a hypoxic but nonischemic hypobaric rat model of pulmonary hypertension. Our data demonstrate that depletion of oxygen or fuel results in repression or induction, respectively, of PGC-1α expression via discrete mechanisms, which may contribute to cardiac energetic derangement during hypoxia, ischemia, and failure.

scholarly journals Leptin Stimulates Fatty Acid Oxidation and Peroxisome Proliferator-Activated Receptor α Gene Expression in Mouse C2C12 Myoblasts by Changing the Subcellular Localization of the α2 Form of AMP-Activated Protein Kinase

2007 ◽  
Vol 27 (12) ◽  
pp. 4317-4327 ◽  
Author(s):  
Atsushi Suzuki ◽  
Shiki Okamoto ◽  
Suni Lee ◽  
Kumiko Saito ◽  
Tetsuya Shiuchi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Subcellular Localization ◽  
Fatty Acid Oxidation ◽  
Metabolic Effects ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Amp Activated Protein Kinase

ABSTRACT Leptin stimulates fatty acid oxidation in skeletal muscle through the activation of AMP-activated protein kinase (AMPK) and the induction of gene expression, such as that for peroxisome proliferator-activated receptor α (PPARα). We now show that leptin stimulates fatty acid oxidation and PPARα gene expression in the C2C12 muscle cell line through the activation of AMPK containing the α2 subunit (α2AMPK) and through changes in the subcellular localization of this enzyme. Activated α2AMPK containing the β1 subunit was shown to be retained in the cytoplasm, where it phosphorylated acetyl coenzyme A carboxylase and thereby stimulated fatty acid oxidation. In contrast, α2AMPK containing the β2 subunit transiently increased fatty acid oxidation but underwent rapid translocation to the nucleus, where it induced PPARα gene transcription. A nuclear localization signal and Thr172 phosphorylation of α2 were found to be essential for nuclear translocation of α2AMPK, whereas the myristoylation of β1 anchors α2AMPK in the cytoplasm. The prevention of α2AMPK activation and the change in its subcellular localization inhibited the metabolic effects of leptin. Our data thus suggest that the activation of and changes in the subcellular localization of α2AMPK are required for leptin-induced stimulation of fatty acid oxidation and PPARα gene expression in muscle cells.

scholarly journals The Potential Applications of Peroxisome Proliferator-Activated ReceptorδLigands in Assisted Reproductive Technology

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-6 ◽  
Author(s):  
Jaou-Chen Huang
Keyword(s):  
Assisted Reproductive Technology ◽  
Reproductive Function ◽  
Reproductive Technology ◽  
Embryonic Cell ◽  
Preimplantation Embryos ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Potential Applications ◽  
And Function

Peroxisome proliferator-activated receptorδ(PPARδ, also known as PPARβ) has ubiquitous distribution and extensive biological functions. The reproductive function of PPARδwas first revealed in the uterus at the implantation site. Since then, PPARδand its ligand have been discovered in all reproductive tissues, including the gametes and the preimplantation embryos. PPARδin preimplantation embryos is normally activated by oviduct-derived PPARδligand. PPARδactivation is associated with an increase in embryonic cell proliferation and a decrease in programmed cell death (apoptosis). On the other hand, the role of PPARδand its ligand in gamete formation and function is less well understood. This review will summarize the reproductive functions of PPARδand project its potential applications in assisted reproductive technology.

scholarly journals PPARγin Bacterial Infections: A Friend or Foe?

PPAR Research ◽  
2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Aravind T. Reddy ◽  
Sowmya P. Lakshmi ◽  
Raju C. Reddy
Keyword(s):  
Bacterial Infections ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Antibacterial Properties ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Therapeutic Modalities ◽  
Anti Inflammatory ◽  
And Function

Peroxisome proliferator-activated receptorγ(PPARγ) is now recognized as an important modulator of leukocyte inflammatory responses and function. Its immunoregulatory function has been studied in a variety of contexts, including bacterial infections of the lungs and central nervous system, sepsis, and conditions such as chronic granulomatous disease. Although it is generally believed that PPARγactivation is beneficial for the host during bacterial infections via its anti-inflammatory and antibacterial properties, PPARγagonists have also been shown to dampen the host immune response and in some cases exacerbate infection by promoting leukocyte apoptosis and interfering with leukocyte migration and infiltration. In this review we discuss the role of PPARγand its activation during bacterial infections, with focus on the potential of PPARγagonists and perhaps antagonists as novel therapeutic modalities. We conclude that adjustment in the dosage and timing of PPARγagonist administration, based on the competence of host antimicrobial defenses and the extent of inflammatory response and tissue injury, is critical for achieving the essential balance between pro- and anti-inflammatory effects on the immune system.

scholarly journals The E3 ligase MARCH5 is a PPARγ target gene that regulates mitochondria and metabolism in adipocytes

2019 ◽  
Vol 316 (2) ◽  
pp. E293-E304 ◽  
Author(s):  
Simon T. Bond ◽  
Sarah C. Moody ◽  
Yingying Liu ◽  
Mete Civelek ◽  
Claudio J. Villanueva ◽  
...  
Keyword(s):  
Mitochondrial Function ◽  
Mitochondrial Dynamics ◽  
Mouse Strains ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolic Genes ◽  
And Function

Mitochondrial dynamics refers to the constant remodeling of mitochondrial populations by multiple cellular pathways that help maintain mitochondrial health and function. Disruptions in mitochondrial dynamics often lead to mitochondrial dysfunction, which is frequently associated with disease in rodents and humans. Consistent with this, obesity is associated with reduced mitochondrial function in white adipose tissue, partly via alterations in mitochondrial dynamics. Several proteins, including the E3 ubiquitin ligase membrane-associated RING-CH-type finger 5 (MARCH5), are known to regulate mitochondrial dynamics; however, the role of these proteins in adipocytes has been poorly studied. Here, we show that MARCH5 is regulated by peroxisome proliferator-activated receptor-γ (PPARγ) during adipogenesis and is correlated with fat mass across a panel of genetically diverse mouse strains, in ob/ob mice, and in humans. Furthermore, manipulation of MARCH5 expression in vitro and in vivo alters mitochondrial function, affects cellular metabolism, and leads to differential regulation of several metabolic genes. Thus our data demonstrate an association between mitochondrial dynamics and metabolism that defines MARCH5 as a critical link between these interconnected pathways.

scholarly journals Estrogen-Related Receptor α Directs Peroxisome Proliferator-Activated Receptor α Signaling in the Transcriptional Control of Energy Metabolism in Cardiac and Skeletal Muscle

2004 ◽  
Vol 24 (20) ◽  
pp. 9079-9091 ◽  
Author(s):  
Janice M. Huss ◽  
Inés Pineda Torra ◽  
Bart Staels ◽  
Vincent Giguère ◽  
Daniel P. Kelly
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Target Genes ◽  
Cellular Fatty Acid ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Oxidation Rates

ABSTRACT Estrogen-related receptors (ERRs) are orphan nuclear receptors activated by the transcriptional coactivator peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), a critical regulator of cellular energy metabolism. However, metabolic target genes downstream of ERRα have not been well defined. To identify ERRα-regulated pathways in tissues with high energy demand such as the heart, gene expression profiling was performed with primary neonatal cardiac myocytes overexpressing ERRα. ERRα upregulated a subset of PGC-1α target genes involved in multiple energy production pathways, including cellular fatty acid transport, mitochondrial and peroxisomal fatty acid oxidation, and mitochondrial respiration. These results were validated by independent analyses in cardiac myocytes, C2C12 myotubes, and cardiac and skeletal muscle of ERRα−/− mice. Consistent with the gene expression results, ERRα increased myocyte lipid accumulation and fatty acid oxidation rates. Many of the genes regulated by ERRα are known targets for the nuclear receptor PPARα, and therefore, the interaction between these regulatory pathways was explored. ERRα activated PPARα gene expression via direct binding of ERRα to the PPARα gene promoter. Furthermore, in fibroblasts null for PPARα and ERRα, the ability of ERRα to activate several PPARα targets and to increase cellular fatty acid oxidation rates was abolished. PGC-1α was also shown to activate ERRα gene expression. We conclude that ERRα serves as a critical nodal point in the regulatory circuitry downstream of PGC-1α to direct the transcription of genes involved in mitochondrial energy-producing pathways in cardiac and skeletal muscle.

scholarly journals LRRK2 Regulates CPT1A to Promote β-Oxidation in HepG2 Cells

Molecules ◽  
2020 ◽  
Vol 25 (18) ◽  
pp. 4122 ◽  
Author(s):  
Chiao-Wei Lin ◽  
Yu-Ju Peng ◽  
Yuan-Yu Lin ◽  
Harry John Mersmann ◽  
Shih-Torng Ding
Keyword(s):  
Lipid Metabolism ◽  
Hepg2 Cells ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Cytokine Tumor Necrosis Factor ◽  
Factor Α ◽  
Amp Activated Protein Kinase ◽  
Necrosis Factor

Leucine-rich repeat kinase 2 (LRRK2) is involved in lipid metabolism; however, the role of LRRK2 in lipid metabolism to affect non-alcoholic fatty liver disease (NAFLD) is still unclear. In the mouse model of NAFLD induced by a high-fat diet, we observed that LRRK2 was decreased in livers. In HepG2 cells, exposure to palmitic acid (PA) down-regulated LRRK2. Overexpression and knockdown of LRRK2 in HepG2 cells were performed to further investigate the roles of LRRK2 in lipid metabolism. Our results showed that β-oxidation in HepG2 cells was promoted by LRRK2 overexpression, whereas LRRK2 knockdown inhibited β-oxidation. The critical enzyme of β-oxidation, carnitine palmitoyltransferase 1A (CPT1A), was positively regulated by LRRK2. Our data suggested that the regulation of CPT1A by LRRK2 may be via the activation of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα). The overexpression of LRRK2 reduced the concentration of a pro-inflammatory cytokine, tumor necrosis factor α (TNFα), induced by PA. The increase in β-oxidation may promote lipid catabolism to suppress inflammation induced by PA. These results indicated that LRRK2 participated in the regulation of β-oxidation and suggested that the decreased LRRK2 may promote inflammation by suppressing β-oxidation in the liver.

scholarly journals Interferon-Stimulated Gene ISG12b1 Inhibits Adipogenic Differentiation and Mitochondrial Biogenesis in 3T3-L1 Cells

Endocrinology ◽  
2008 ◽  
Vol 150 (3) ◽  
pp. 1217-1224 ◽  
Author(s):  
Bing Li ◽  
Jonghyun Shin ◽  
Kichoon Lee
Keyword(s):  
Mitochondrial Biogenesis ◽  
Adipogenic Differentiation ◽  
Peroxisome Proliferator ◽  
Mitochondrial Transcription ◽  
Peroxisome Proliferator Activated Receptor ◽  
And Function ◽  
Adipocyte Development

Microarray analysis was performed to find a new group of genes or pathways that might be important in adipocyte development and metabolism. Among them, a mouse interferon-stimulated gene 12b1 (ISG12b1) is expressed at a 400-fold higher level in adipocytes compared with stromal-vascular cells. It is predominantly expressed in adipose tissue among other tissues we tested. Developmentally, ISG12b1 mRNA expression was initially inhibited followed by a dramatic induction during both in vivo and in vitro adipogenic differentiation. Adenovirus-mediated overexpression of ISG12b1 inhibited adipogenic differentiation in 3T3-L1 cells as shown by decreased lipid staining with Oil-Red-O and reduction in adipogenic marker proteins including peroxisome proliferator-activated receptor-γ (PPARγ), and CCAAT/enhancer-binding protein-α (C/EBPα). Our bioinformatics analysis for the predicted localization of ISG12b1 protein suggested the mitochondrial localization, which was confirmed by the colocalization of hemagglutinin-tagged ISG12b1 protein with mitochondrial marker MitoTracker. In addition, ISG12b1 protein was exclusively detected in protein extract from the fractionated mitochondria by Western blot analysis. Furthermore, overexpression of ISG12b1 in adipocytes reduced mitochondrial DNA content and gene expression of mitochondrial transcription factor A (mtTFA), nuclear respiratory factor 1 (NRF1), and cytochrome oxidase II, suggesting an inhibitory role of ISG12b1 in mitochondrial biogenesis and function. Activation of mitochondrial biogenesis and function by treatment with PPARγ and PPARα agonists in 3T3-L1 cells and cold exposure in mice induced mitochondrial transcription factors and reduced ISG12 expression. These data demonstrated that mitochondrial-localized ISG12b1 protein inhibits adipocyte differentiation and mitochondrial biogenesis and function, implying the important role of mitochondrial function in adipocyte development and associated diseases. ISG12b1 is predominantly expressed in adipocytes and dramatically induced at the terminal stage of adipogenesis. Functionally, mitochondria-localized ISG12b1 inhibits adipogenic differentiation and mitochondria biogenesis.

Nuclear receptor-mediated regulation of lipid droplet-associated protein gene expression in adipose tissue

2013 ◽  
Vol 14 (3) ◽  
Author(s):  
Mark Christian
Keyword(s):  
Gene Expression ◽  
Estrogen Receptor Α ◽  
Peroxisome Proliferator ◽  
Adipose Tissues ◽  
Peroxisome Proliferator Activated Receptor ◽  
Genes Encoding ◽  
Associated Proteins ◽  
High Throughput Dna Sequencing ◽  
And Function ◽  
White Fat

AbstractIn adipose tissues, nuclear receptors (NRs) have important metabolic actions on cellular lipid-storing capacity through targeted gene regulation. Lipid droplets (LDs) are the organelles for intracellular triacylglycerol (TAG) storage and are present in all eukaryotic cells. They are small in most cells, but in white adipocytes, they can occupy 90% of the cytoplasm. LDs consist of a TAG core surrounded by a phospholipid monolayer and an array of associated proteins that determine size, stability, inter-droplet interaction, and lipid storage capacity. The genes that encode these proteins are more highly expressed in brown compared with white fat, correlating with the greater LD surface area in multilocular brown adipocytes. Gene expression profiling reveals that most NRs are present in adipose tissues, with some showing greater expression in brown compared with white fat, including peroxisome proliferator-activated receptor (PPAR) α, estrogen-related receptor α, and NURR1. NR signaling is important for the regulated expression of most genes that encode LD-associated proteins. For example, estradiol signals via estrogen receptor α to regulate the levels of PLIN1 and the lipase ATGL controlling LD size and total lipid accumulation. PPARγ is essential for adipocyte differentiation and function, and analysis of data obtained through chromatin immunoprecipitation followed by high-throughput DNA sequencing shows that it binds to the promoters of many genes encoding LD proteins in adipocytes. Of these genes, the greatest PPARγ binding was to regulatory regions for

scholarly journals The Peroxisome Proliferator-Activated Receptor N-Terminal Domain Controls Isotype-Selective Gene Expression and Adipogenesis

2006 ◽  
Vol 20 (6) ◽  
pp. 1261-1275 ◽  
Author(s):  
Sarah Hummasti ◽  
Peter Tontonoz
Keyword(s):  
Gene Expression ◽  
Fatty Acid ◽  
Target Genes ◽  
Biological Effects ◽  
Binding Domain ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
N Terminus

Abstract Peroxisome proliferator-activated receptors (PPARγ, PPARα, and PPARδ) are important regulators of lipid metabolism. Although they share significant structural similarity, the biological effects associated with each PPAR isotype are distinct. For example, PPARα and PPARδ regulate fatty acid catabolism, whereas PPARγ controls lipid storage and adipogenesis. The different functions of PPARs in vivo can be explained at least in part by the different tissue distributions of the three receptors. The question of whether the receptors have different intrinsic activities and regulate distinct target genes, however, has not been adequately explored. We have engineered cell lines that express comparable amounts of each receptor. Transcriptional profiling of these cells in the presence of selective agonists reveals partially overlapping but distinct patterns of gene regulation by the three PPARs. Moreover, analysis of chimeric receptors points to the N terminus of each receptor as the key determinant of isotype-selective gene expression. For example, the N terminus of PPARγ confers the ability to promote adipocyte differentiation when fused to the PPARδ DNA binding domain and ligand binding domain, whereas the N terminus of PPARδ leads to the inappropriate expression of fatty acid oxidation genes in differentiated adipocytes when fused to PPARγ. Finally, we demonstrate that the N terminus of each receptor functions in part to limit receptor activity because deletion of the N terminus leads to nonselective activation of target genes. A more detailed understanding of the mechanisms by which the individual PPARs differentially regulate gene expression should aid in the design of more effective drugs, including tissue- and target gene-selective PPAR modulators.

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