AMPK activation enhances PPARα activity to inhibit cardiac hypertrophy via ERK1/2 MAPK signaling pathway

Wang, Mengqi; Pei, Zhaohui; Zhang, Aixia; Zhou, Yutian; Cai, Xingming; Chen, Baolin; Liu, Guanjie; Mai, Weiyi; Wei, Jianrui; Dong, Yugang

doi:10.1016/j.abb.2011.04.010

Cited by 73 publications

(62 citation statements)

References 34 publications

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“…Additional studies are required to elucidate the specific mechanism through which Erk regulates PDK4 mRNA, the levels of which have been shown to be controlled by numerous proteins and signaling pathways (Abbot et al 2005;Sugden and Holness 2006;Roche and Hiromasa 2007). Some transcriptional regulators of PDK4, such as retinoid X receptor and FOXO1, have previously been found to be negatively regulated by Erk signaling (Arnaud et al 2004;Coll et al 2006;Asada et al 2007;Burgermeister et al 2007;Macoritto et al 2008;Shankar et al 2008;Meng et al 2011). Importantly, previous studies implicating PI3K/Akt as a negative regulator of PDK4 expression were performed in myocytes (Puthanveetil et al 2010), which must generate significant energy (i.e., ATP) from glucose in response to insulin to function properly (Latronico et al 2004).…”

Section: Discussionmentioning

confidence: 99%

Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation

Grassian¹,

Metallo²,

Coloff³

et al. 2011

Genes Dev.

169

137

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Loss of extracellular matrix (ECM) attachment leads to metabolic impairments that limit cellular energy production. Characterization of the metabolic alterations induced by ECM detachment revealed a dramatic decrease in uptake of glucose, glutamine, and pyruvate, and a consequent decrease in flux through glycolysis, the pentose phosphate pathway, and the tricarboxylic acid (TCA) cycle. However, flux through pyruvate dehydrogenase (PDH) is disproportionally decreased, concomitant with increased expression of the PDH inhibitory kinase, PDH kinase 4 (PDK4), and increased carbon secretion. Overexpression of ErbB2 maintains PDH flux by suppressing PDK4 expression in an Erk-dependent manner, and Erk signaling also regulates PDH flux in ECMattached cells. Additionally, epidermal growth factor (EGF), a potent inducer of Erk, positively regulates PDH flux through decreased PDK4 expression. Furthermore, overexpression of PDK4 in ECM-detached cells suppresses the ErbB2-mediated rescue of ATP levels, and in attached cells, PDK4 overexpression decreases PDH flux, de novo lipogenesis, and cell proliferation. Mining of microarray data from human tumor data sets revealed that PDK4 mRNA is commonly down-regulated in tumors compared with their tissues of origin. These results identify a novel mechanism by which ECM attachment, growth factors, and oncogenes modulate the metabolic fate of glucose by controlling PDK4 expression and PDH flux to influence proliferation.

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Section: Discussionmentioning

confidence: 99%

Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation

Grassian¹,

Metallo²,

Coloff³

et al. 2011

Genes Dev.

169

137

View full text Add to dashboard Cite

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“…5). PPAR␣ activators fenofibrate and Wy-14,643 activate the AMPK signaling pathway (53,54,70,71). We reported here the attenuation of hepatocyte proliferation in the liver of wild-type mice by compound C; they were fed a diet containing the PPAR␣ activator Wy-14,643, suggesting that AMPK is also involved in the PPAR␣ pathway.…”

Section: Discussionmentioning

confidence: 72%

“…In addition to their function as PPAR␣ activators, these PPAR␣ agonists also induce AMPK phosphorylation in some cell types (51)(52)(53)(54). To determine whether AMPK activation is involved in PPAR␣ ligand-induced fatty acid oxidation enzymes, mice were fed with a diet containing Wy-14,643 for 3 days, and they also received compound C injections intraperitoneally once daily for 3 days (Fig.…”

Section: Ampk Forms a Complex With Med1 In Vivo And Binds Directly Tomentioning

confidence: 99%

The Med1 Subunit of the Mediator Complex Induces Liver Cell Proliferation and Is Phosphorylated by AMP Kinase

Viswakarma

Jia

Bai

et al. 2013

Journal of Biological Chemistry

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Background:The Med1 subunit of the Mediator complex orchestrates metabolic pathways of energy metabolism. Results: Overexpression of Med1 in liver enhances hepatocyte proliferation and the cellular energy sensor AMPK phosphorylates Med1. Conclusion: Med1 is essential for hepatocellular proliferation and energy homeostasis downstream to AMPK. Significance: Med1 and its phosphorylation by AMPK may have important implications in the pathophysiology of liver.

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“…It has been known that activation of AMPK prevents aortic banding-induced cardiac hypertrophy 40 by enhancement of peroxisome proliferator-activated receptor-α signaling in the heart 31 and that AMPK induces SHP in response to metformin in hepatocytes. 27 In the present study, we also observed that metformin activates AMPK in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

“…30 Metformin also has antihypertrophic action through AMP-activated protein kinase (AMPK) activation, which involves mitogen-activated protein kinase 1/2 and mammalian target of rapamycin signaling. 31,32 In addition to these signaling pathways, we postulated that SHP is also involved in the beneficial action of metformin.…”

Section: Metformin Induces Shp In Cardiomyocytes In An Amp-activated mentioning

confidence: 99%

Small Heterodimer Partner Blocks Cardiac Hypertrophy by Interfering With GATA6 Signaling

Nam

Kim

Joung

et al. 2014

Circulation Research

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Cardiac hypertrophy is an increase in the individual cellular volume of the heart and is an adaptive response to exogenous stresses. The increase in cellular volume is associated with reactivation of the fetal gene program, which is finely regulated by diverse cardiac transcription factors.1 Specifically, GATA4, GATA6, myocyte enhancer factor 2C, nuclear factor of activated T cells, NK2 homeobox 5, and serum response factor have been shown to be involved in the development of cardiac hypertrophy.1 GATA4 and GATA6 are heart-specific transcription factors that regulate pathological cardiac hypertrophy in association with atrial natriuretic factor (ANF) expression.2,3 Transgenic mice that overexpress GATA4 in the heart show cardiac hypertrophy, 4 and GATA4 activity is regulated by physical interaction with other transcription factors, such as serum response factor, NK2 homeobox 5, and myocyte enhancer factor 2.5-7 GATA6 also induces pathological cardiac hypertrophy, which was demonstrated by recent studies of cardiac-specific overexpression of GATA6 in mice. 3In addition to effects as transcription factors, some of these factors also act as nuclear receptors that provide signal-mediated responsiveness to endogenous or exogenous ligands. For example, peroxisome proliferator-activated receptor-α or steroid receptors respond to a ligand and then mediate diverse cellular events as well as metabolic regulation.8,9 Not surprisingly, these nuclear receptors also play important roles in various organs, and therapeutic applications of their modulators are growing. The nuclear receptors are classified depending on their structural similarities. Interestingly, 1 group of nuclear receptors is termed the orphan nuclear receptors. In contrast with the other nuclear receptors that have endogenous ligands

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AMPK activation enhances PPARα activity to inhibit cardiac hypertrophy via ERK1/2 MAPK signaling pathway

Cited by 73 publications

References 34 publications

Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation

Erk regulation of pyruvate dehydrogenase flux through PDK4 modulates cell proliferation

The Med1 Subunit of the Mediator Complex Induces Liver Cell Proliferation and Is Phosphorylated by AMP Kinase

Small Heterodimer Partner Blocks Cardiac Hypertrophy by Interfering With GATA6 Signaling

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