scholarly journals Evaluation of the role of peroxisome-proliferator-activated receptor α in the regulation of cardiac pyruvate dehydrogenase kinase 4 protein expression in response to starvation, high-fat feeding and hyperthyroidism

2002 ◽  
Vol 364 (3) ◽  
pp. 687-694 ◽  
Author(s):  
Mark J. HOLNESS ◽  
Nicholas D. SMITH ◽  
Karen BULMER ◽  
Teresa HOPKINS ◽  
Geoffrey F. GIBBONS ◽  
...  
Keyword(s):  
Protein Expression ◽  
Pyruvate Dehydrogenase ◽  
Fold Increase ◽  
Pyruvate Dehydrogenase Kinase ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor

Inactivation of cardiac pyruvate dehydrogenase complex (PDC) after prolonged starvation and in response to hyperthyroidism is associated with enhanced protein expression of pyruvate dehydrogenase kinase (PDK) isoform 4. The present study examined the potential role of peroxisome-proliferator-activated receptor α (PPARα) in adaptive modification of cardiac PDK4 protein expression after starvation and in hyperthyroidism. PDK4 protein expression was analysed by immunoblotting in homogenates of hearts from fed or 48h-starved rats, rats rendered hyperthyroid by subcutaneous injection of tri-iodothyronine and a subgroup of euthyroid rats maintained on a high-fat/low-carbohydrate diet, with or without treatment with the PPARα agonist WY14,643. In addition, PDK4 protein expression was analysed in hearts from fed, 24h-starved or 6h-refed wild-type or PPARα-null mice. PPARα activation by WY14,643 in vivo over the timescale of the response to starvation failed to up-regulate cardiac PDK4 protein expression in rats maintained on standard diet (WY14,643, 1.1-fold increase; starvation, 1.8-fold increase) or influence the cardiac PDK4 response to starvation. By contrast, PPARα activation by WY14,643 in vivo significantly enhanced cardiac PDK4 protein expression in rats maintained on a high-fat diet, which itself increased cardiac PDK4 protein expression. PPARα deficiency did not abolish up-regulation of cardiac PDK4 protein expression in response to starvation (2.9-fold increases in both wild-type and PPARα-null mice). Starvation and hyperthyroidism exerted additive effects on cardiac PDK4 protein expression, but PPARα activation by WY14,643 did not influence the response of cardiac PDK4 protein expression to hyperthyroidism in either the fed or starved state. Our data support the hypothesis that cardiac PDK4 protein expression is regulated, at least in part, by a fatty acid-dependent, PPARα-independent mechanism and strongly implicate a fall in insulin in either initiating or facilitating the response of cardiac PDK4 protein expression to starvation.

scholarly journals Up-regulation of pyruvate dehydrogenase kinase isoform 4 (PDK4) protein expression in oxidative skeletal muscle does not require the obligatory participation of peroxisome-proliferator-activated receptor α (PPARα)

2002 ◽  
Vol 366 (3) ◽  
pp. 839-846 ◽  
Author(s):  
Mark J. HOLNESS ◽  
Karen BULMER ◽  
Geoffrey F. GIBBONS ◽  
Mary C. SUGDEN
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Pyruvate Dehydrogenase ◽  
Skeletal Muscles ◽  
Pyruvate Dehydrogenase Kinase ◽  
Glucose Disposal ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Anterior Tibialis

In insulin deficiency, increased lipid delivery and oxidation suppress skeletal-muscle glucose oxidation by inhibiting pyruvate dehydrogenase complex (PDC) activity via enhanced protein expression of pyruvate dehydrogenase kinase (PDK) isoform 4, which phosphorylates (and inactivates) PDC. Signalling via peroxisome-proliferator-activated receptor α (PPARα) is an important component of the mechanism enhancing hepatic and renal PDK4 protein expression. Activation of PPARα in gastrocnemius, a predominantly fast glycolytic (FG) muscle, also increases PDK4 expression, an effect that, if extended to all muscles, would be predicted to drastically restrict whole-body glucose disposal. Paradoxically, chronic activation of PPARα by WY14,643 treatment improves glucose utilization by muscles of insulin-resistant high-fat-fed rats. In the resting state, oxidative skeletal muscles are quantitatively more important for glucose disposal than FG muscles. We evaluated the participation of PPARα in regulating PDK4 protein expression in slow oxidative (SO) skeletal muscle (soleus) and fast oxidative-glycolytic (FOG) skeletal muscle (anterior tibialis) containing a high proportion of oxidative fibres. In the fed state, acute (24h) activation of PPARα by WY14,643 in vivo failed to modify PDK4 protein expression in soleus, but modestly enhanced PDK4 protein expression in anterior tibialis. Starvation enhanced PDK4 protein expression in both muscles, with the greater response in anterior tibialis. WY14,643 treatment in vivo during starvation did not further enhance upregulation of PDK4 protein expression in either muscle type. Enhanced PDK4 protein expression after starvation was retained in SO and FOG skeletal muscles of PPARα-deficient mice. Our data indicate that PDK4 protein expression in oxidative skeletal muscle is regulated by a lipid-dependent mechanism that is not obligatorily dependent on signalling via PPARα.

Abstract 301: Initial Increase of Klf5 and Ppara Expression After Myocardial Ischemia/Reperfusion in Mice Appears to be Critical for Survival

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Christine J Pol ◽  
Mesele-Christina Valenti ◽  
Sarah M Schumacher ◽  
Ancai Yuan ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Ischemia Reperfusion ◽  
Pyruvate Dehydrogenase Kinase ◽  
Acid Oxidation ◽  
Initial Increase ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Myocardial Ischemia Reperfusion

Krüppel-like factors (KLF) have important roles in metabolism. We previously found that KLF5 is a positive transcriptional regulator of peroxisome proliferator-activated receptor α ( Ppara) , a central regulator of cardiac fatty acid oxidation (FAO). Mice with cardiomyocyte-specific Klf5 ablation ( α MHC-Klf5 -/- ) had reduced cardiac Ppara expression and FAO. At age 6-12 months these mice develop distinct cardiac dysfunction. The role of PPARα activation in I/R injury is unclear as both beneficial and detrimental effects have been reported. We aimed to study if Ppara expression changes during I/R are driven by KLF5 and explore its protective or detrimental role. Wild type mice were subjected to in vivo I/R or sham surgery. I/R resulted in an initial increase in Ppara , and its target gene pyruvate dehydrogenase kinase 4 ( Pdk4) mRNA after 2h reperfusion, followed by decreased expression after 24h reperfusion. The Ppara expression is associated with parallel changes in cardiac Klf5 mRNA expression. Concurrent, there was a decrease of cardiac FAO-related genes carnitine palmitoyl-transferase 1β ( Cpt1b), very long chain acyl-CoA dehydrogenase (Vlcad), and acyl-CoA oxidase ( Aox) in mice with I/R. To define the cell type causing the temporal changes in Klf5 and Ppara after I/R we isolated primary cardiomyocytes and fibroblasts. Our data suggest a similar effect in primary isolated cardiomyocytes only. Klf5 mRNA expression is increased after 2 hour hypoxia and normalized after 4 hour re-oxygenation in cardiomyocytes, whereas there are no changes after hypoxia/normoxia in fibroblasts. To assess the importance of cardiomyocyte KLF5 in I/R we used α MHC-Klf5 -/- mice. Interestingly, despite reduced FAO, 7 month old αMHC-Klf5 -/- mice subjected to I/R had a marked increase in mortality; 4 of 7 αMHC-Klf5 -/- mice died within the first 24h of reperfusion while no mortality was observed in age-matched wild type mice that underwent I/R. In conclusion, I/R is associated with an increase in Klf5 and Ppara in the first hours of reperfusion followed by a decrease in Klf5 and Ppara , likely accounted for by cardiomyocytes. Increased mortality for α MHC-Klf5 -/- mice with I/R injury suggests that the initial increase may be an adaptive response that is critical for survival.

Control of cardiac pyruvate dehydrogenase activity in peroxisome proliferator-activated receptor-α transgenic mice

2003 ◽  
Vol 285 (1) ◽  
pp. H270-H276 ◽  
Author(s):  
Teresa A. Hopkins ◽  
Mary C. Sugden ◽  
Mark J. Holness ◽  
Ray Kozak ◽  
Jason R. B. Dyck ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Pyruvate Dehydrogenase ◽  
Glucose Oxidation ◽  
Pyruvate Dehydrogenase Kinase ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Oxidation Rates

The pyruvate dehydrogenase enzyme complex (PDC) is rate limiting for glucose oxidation in the heart. Inhibition of PDC by end-product feedback and phosphorylation by pyruvate dehydrogenase kinase (PDK) operate in concert to inhibit PDC activity. Because the transcriptional regulator peroxisome proliferator-activated receptor (PPAR)-α increases PDK expression in some tissues, we examined what role PPAR-α has in regulating glucose oxidation in hearts from mice overexpressing PPAR-α (MHC-PPAR-α mice). Glucose oxidation rates were decreased in isolated working hearts from MHC-PPAR-α mice compared with wild-type littermates (428 ± 113 vs. 771 ± 63 nmol · g dry weight-1 · min-1, respectively), which was accompanied by a parallel increase in fatty acid oxidation. However, there was no difference in PDC activity between MHC-PPAR-α and wild-type animals, even though the expression of the PDK isoform PDK1 was increased in MHC-PPAR-α mice. Glucose oxidation rates in both MHC-PPAR-α and wild-type mouse hearts were decreased after 48-h fasting (which increases PPAR-α expression) or by treatment of mice with the PPAR-α agonist WY-14,643 for 1 wk. Despite this, PDC activity in both animal groups was not altered. Taken together, these data suggest that glucose oxidation rates in the heart can be dramatically altered independent of PDK phosphorylation and inhibition of PDC by PDK. It also suggests that PPAR-α activation decreases glucose oxidation in hearts mainly by decreasing the flux of pyruvate through PDC due to negative feedback of PDC by fatty acid oxidation reaction products rather than by the phosphorylated state of the PDC complex.

scholarly journals Hepatic sirtuin 1 is dispensable for fibrate-induced peroxisome proliferator-activated receptor-α function in vivo

2014 ◽  
Vol 306 (7) ◽  
pp. E824-E837 ◽  
Author(s):  
Jessica A. Bonzo ◽  
Chad Brocker ◽  
Changtao Jiang ◽  
Rui-Hong Wang ◽  
Chu-Xia Deng ◽  
...  
Keyword(s):  
Gene Expression ◽  
Knockout Mice ◽  
High Fat Diet ◽  
Target Genes ◽  
Sirtuin 1 ◽  
Peroxisome Proliferator ◽  
Wild Type ◽  
High Fat ◽  
Peroxisome Proliferator Activated Receptor

Peroxisome proliferator-activated receptor-α (PPARα) mediates metabolic remodeling, resulting in enhanced mitochondrial and peroxisomal β-oxidation of fatty acids. In addition to the physiological stimuli of fasting and high-fat diet, PPARα is activated by the fibrate class of drugs for the treatment of dyslipidemia. Sirtuin 1 (SIRT1), an important regulator of energy homeostasis, was downregulated in fibrate-treated wild-type mice, suggesting PPARα regulation of Sirt1 gene expression. The impact of SIRT1 loss on PPARα functionality in vivo was assessed in hepatocyte-specific knockout mice that lack the deacetylase domain of SIRT1 ( Sirt1 ΔLiv). Knockout mice were treated with fibrates or fasted for 24 h to activate PPARα. Basal expression of the PPARα target genes Cyp4a10 and Cyp4a14 was reduced in Sirt1 ΔLiv mice compared with wild-type mice. However, no difference was observed between wild-type and Sirt1 ΔLiv mice in either fasting- or fibrate-mediated induction of PPARα target genes. Similar to the initial results, there was no difference in fibrate-activated PPARα gene induction. To assess the relationship between SIRT1 and PPARα in a pathophysiological setting, Sirt1 ΔLiv mice were maintained on a high-fat diet for 14 wk, followed by fibrate treatment. Sirt1 ΔLiv mice exhibited increased body mass compared with control mice. In the context of a high-fat diet, Sirt1 ΔLiv mice did not respond to the cholesterol-lowering effects of the fibrate treatment. However, there were no significant differences in PPARα target gene expression. These results suggest that, in vivo, SIRT1 deacetylase activity does not significantly impact induced PPARα activity.

scholarly journals Investigation of potential mechanisms regulating protein expression of hepatic pyruvate dehydrogenase kinase isoforms 2 and 4 by fatty acids and thyroid hormone

2003 ◽  
Vol 369 (3) ◽  
pp. 687-695 ◽  
Author(s):  
Mark J. HOLNESS ◽  
Karen BULMER ◽  
Nicholas D. SMITH ◽  
Mary C. SUGDEN
Keyword(s):  
Thyroid Hormone ◽  
Protein Expression ◽  
Pyruvate Dehydrogenase ◽  
Hormone Receptors ◽  
Pyruvate Dehydrogenase Complex ◽  
Pyruvate Dehydrogenase Kinase ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Cpt I ◽  
Fat Feeding

Liver contains two pyruvate dehydrogenase kinases (PDKs), namely PDK2 and PDK4, which regulate glucose oxidation through inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC). Starvation increases hepatic PDK2 and PDK4 protein expression, the latter occurring, in part, via a mechanism involving peroxisome proliferator-activated receptor-α (PPARα). High-fat feeding and hyperthyroidism, which increase circulating lipid supply, enhance hepatic PDK2 protein expression, but these increases are insufficient to account for observed increases in hepatic PDK activity. Enhanced expression of PDK4, but not PDK2, occurs in part via a mechanism involving PPAR-α. Heterodimerization partners for retinoid X receptors (RXRs) include PPARα and thyroid-hormone receptors (TRs). We therefore investigated the responses of hepatic PDK protein expression to high-fat feeding and hyperthyroidism in relation to hepatic lipid delivery and disposal. High-fat feeding increased hepatic PDK2, but not PDK4, protein expression whereas hyperthyroidism increased both hepatic PDK2 and PDK4 protein expression. Both manipulations decreased the sensitivity of hepatic carnitine palmitoyltransferase I (CPT I) to suppression by malonyl-CoA, but only hyperthyrodism elevated plasma fatty acid and ketone-body concentrations and CPT I maximal activity. Administration of the selective PPAR-α activator WY14,643 significantly increased PDK4 protein to a similar extent in both control and high-fat-fed rats, but WY14,643 treatment and hyperthyroidism did not have additive effects on hepatic PDK4 protein expression. PPARα activation did not influence hepatic PDK2 protein expression in euthyroid rats, suggesting that up-regulation of PDK2 by hyperthyroidism does not involve PPARα, but attenuated the effect of hyperthyroidism to increase hepatic PDK2 expression. The results indicate that hepatic PDK4 up-regulation can be achieved by heterodimerization of either PPARα or TR with the RXR receptor and that effects of PPARα activation on hepatic PDK2 and PDK4 expression favour a switch towards preferential expression of PDK4.

scholarly journals Hypoxic Exposure Increases Energy Expenditure by Increasing Carbohydrate Oxidation in Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Yeram Park ◽  
Deunsol Hwang ◽  
Hun-Young Park ◽  
Jisu Kim ◽  
Kiwon Lim
Keyword(s):  
Glucose Metabolism ◽  
Energy Expenditure ◽  
Pyruvate Dehydrogenase ◽  
Hypoxic Condition ◽  
Open Circuit ◽  
Pyruvate Dehydrogenase Kinase ◽  
Hypoxic Exposure ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

Aims. Hypoxic exposure improves glucose metabolism. We investigated to validate the hypothesis that carbohydrate (CHO) oxidation could increase in mice exposed to severe hypoxic conditions. Methods. Seven-week-old male ICR mice (n=16) were randomly divided into two groups: the control group (CON) was kept in normoxic condition (fraction of inspired O2=21%) and the hypoxia group (HYP) was exposed to hypoxic condition (fraction of inspired O2=12%, ≈altitude of 4,300 m). The CON group was pair-fed with the HYP group. After 3 weeks of hypoxic exposure, we measured respiratory metabolism (energy expenditure and substrate utilization) at normoxic conditions for 24 hours using an open-circuit calorimetry system. In addition, we investigated changes in carbohydrate mechanism-related protein expression, including hexokinase 2 (HK2), pyruvate dehydrogenase (PDH), pyruvate dehydrogenase kinase 4 (PDK4), and regulator of the genes involved in energy metabolism (peroxisome proliferator-activated receptor gamma coactivator 1-alpha, PGC1α) in soleus muscle. Results. Energy expenditure (EE) and CHO oxidation over 24 hours were higher in the HYP group by approximately 15% and 34% (p<0.001), respectively. Fat oxidation was approximately 29% lower in the HYP group than the CON group (p<0.01). Body weight gains were significantly lower in the HYP group than in the CON group (CON vs. HYP; 1.9±0.9 vs. −0.3±0.9; p<0.001). Hypoxic exposure for 3 weeks significantly reduced body fat by approximately 42% (p<0.001). PDH and PGC1α protein levels were significantly higher in the HYP group (p<0.05). Additionally, HK2 was approximately 21% higher in the HYP group. Conclusions. Hypoxic exposure might significantly enhance CHO oxidation by increasing the expression of PDH and HK2. This investigation can be useful for patients with impaired glucose metabolism, such as those with type 2 diabetes.

scholarly journals The Novel Role of PGC1α in Bone Metabolism

2021 ◽  
Vol 22 (9) ◽  
pp. 4670
Author(s):  
Cinzia Buccoliero ◽  
Manuela Dicarlo ◽  
Patrizia Pignataro ◽  
Francesco Gaccione ◽  
Silvia Colucci ◽  
...  
Keyword(s):  
Bone Metabolism ◽  
Osteoblastic Differentiation ◽  
In Vivo Studies ◽  
Peroxisome Proliferator ◽  
Sirtuin 3 ◽  
Peroxisome Proliferator Activated Receptor ◽  
Increased Risk

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that PGC1α deletion negatively affects cortical thickness, trabecular organization and resistance to flexion, resulting in increased risk of fracture. Furthermore, in a mouse model of bone disease, PGC1α activation stimulates osteoblastic gene expression and inhibits atrogene transcription. PGC1α overexpression positively affects the activity of Sirtuin 3, a mitochondrial nicotinammide adenina dinucleotide (NAD)-dependent deacetylase, on osteoblastic differentiation. In vitro, PGC1α overexpression prevents the reduction of mitochondrial density, membrane potential and alkaline phosphatase activity caused by Sirtuin 3 knockdown in osteoblasts. Moreover, PGC1α influences the commitment of skeletal stem cells towards an osteogenic lineage, while negatively affects marrow adipose tissue accumulation. In this review, we will focus on recent findings about PGC1α action on bone metabolism, in vivo and in vitro, and in pathologies that cause bone loss, such as osteoporosis and type 2 diabetes.

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