14,15-EET promotes mitochondrial biogenesis and protects cortical neurons against oxygen/glucose deprivation-induced apoptosis

Wang, Lai; Chen, Man; Yuan, Lin; Xiang, Yuting; Zheng, Ruimao; Zhu, Shi-En

doi:10.1016/j.bbrc.2014.06.022

Cited by 37 publications

(27 citation statements)

References 27 publications

(39 reference statements)

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“…Furthermore, the EET-A mediated increase of PGC-1 α expression was prevented by SnMP, indicating that EET is working through the HO system that controls cellular levels of heme and the potential of heme-mediated terminal adipocyte stem cell differentiation and enlargement. Our results are corroborated by other studies that have shown that EET, together with SIRT1, regulates PGC-1α expression (55–57), suggesting that they are upstream regulators of PGC-1α. Although EET downregulates the BTB And CNC Homology 1, Basic Leucine Zipper Transcription Factor 1 (BACH1), an inhibitory transcriptional regulator of HO-1, in favor of increased HO-1 levels (58) we now show that the EET-mediated action on HO-1 is also dependent on PGC-1α expression.…”

Section: Discussionsupporting

confidence: 91%

“…While treated with EET-A normalized or enhanced these mitochondrial parameters, PGC-1α-deficiency prevented the EET-A-mediated effects, thus indicating that the EET-A-mediated normalization of diet-induced mitochondrial dysfunction is PGC-1α-dependent. Our results linking EETs to mitochondrial viability are supported by a report showing that EETs promote mitochondrial biogenesis and protect neurons from oxidative damage (77). However, to our knowledge our study is the first to show that EETs stimulate mitochondrial fusion associated processes as indicated by the increased expression of Mfn1 and 2, and OPA1.…”

Section: Discussionsupporting

confidence: 86%

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PGC-1 alpha regulates HO-1 expression, mitochondrial dynamics and biogenesis: Role of epoxyeicosatrienoic acid

Singh

Schragenheim

Cao

et al. 2016

Prostaglandins & Other Lipid Mediators

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Background/Objectives Obesity is a risk factor in the development of type 2 diabetes mellitus (DM2), which is associated with increased morbidity and mortality, predominantly as a result of cardiovascular complications. Increased adiposity is a systemic condition characterized by increased oxidative stress (ROS), increased inflammation, inhibition of anti-oxidant genes such as HO-1 and increased degradation of epoxyeicosatrienoic acids (EETs). We previously demonstrated that EETs attenuate mitochondrial ROS. We postulate that EETs increase peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), which controls mitochondrial function, oxidative metabolism and induction of HO-1. Subjects/Methods Cultured murine adipocytes and mice fed a high fat (HF) diet were used to assess functional relationship between EETs, HO-1 and (PGC-1α) using an EET analogue (EET-A) and lentivirus to knock down the PPARGC1A gene. Results EET-A increased PGC-1α and HO-1 in cultured adipocytes and increased the expression of genes involved in thermogenesis and adipocyte browning (UCP1 and PRDM16, respectively). PGC-1α knockdown prevented EET-A-induced HO-1expression, suggesting that PGC-1α is upstream of HO-1. MRI data obtained from fat tissues showed that EET-A administration to mice on a HF diet significantly reduced total body fat content, subcutaneous and visceral fat deposits and reduced the VAT: SAT ratio. Moreover EET-A normalized the VO2 and RQ (VCO2/VO2) in mice fed a HF diet, an effect that was completely prevented in PGC-1α deficient mice. In addition, EET-A increased mitochondrial biogenesis and function as measured by OPA1, MnSOD, Mfn1, Mfn2, and SIRT3, an effect that was inhibited by knockdown of PGC-1α. Conclusion Taken together, our findings show that EET-A increased PGC-1α thereby increasing mitochondrial viability, increased fusion potential thereby providing metabolic protection and increased VO2 consumption in HF-induced obesity in mice, thus demonstrating that the EET-mediated increase in HO-1 levels require PGC-1α expression.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionsupporting

confidence: 86%

PGC-1 alpha regulates HO-1 expression, mitochondrial dynamics and biogenesis: Role of epoxyeicosatrienoic acid

Singh

Schragenheim

Cao

et al. 2016

Prostaglandins & Other Lipid Mediators

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show abstract

“…Our observation linking EETs to mitochondrial viability and fusion potential is supported by the demonstration that EETs protect neurons from oxidative damage while stimulating mitochondrial biogenesis [39]. Approximately 90% of cellular ROS are generated by the mitochondria and contribute to the mitochondrial energy metabolism [23].…”

Section: Discussionmentioning

confidence: 68%

Downregulation of PGC-1αPrevents the Beneficial Effect of EET-Heme Oxygenase-1 on Mitochondrial Integrity and Associated Metabolic Function in Obese Mice

Singh

Bellner

Vanella

et al. 2016

Journal of Nutrition and Metabolism

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Background/Objectives. Obesity and metabolic syndrome and associated adiposity are a systemic condition characterized by increased mitochondrial dysfunction, inflammation, and inhibition of antioxidant genes, HO-1, and EETs levels. We postulate that EETs attenuate adiposity by stimulating mitochondrial function and induction of HO-1 via activation of PGC-1α in adipose and hepatic tissue. Methods. Cultured murine adipocytes and mice fed a high fat (HF) diet were used to assess the functional relationship among EETs, PGC-1α, HO-1, and mitochondrial signaling using an EET-agonist (EET-A) and PGC-1α-deficient cells and mice using lentiviral PGC-1α(sh). Results. EET-A is a potent inducer of PGC-1α, HO-1, mitochondrial biogenesis (cytochrome oxidase subunits 1 and 4 and SIRT3), fusion proteins (Mfn 1/2 and OPA1) and fission proteins (DRP1 and FIS1) (p < 0.05), fasting glucose, BW, and blood pressure. These beneficial effects were prevented by administration of lenti-PGC-1α(sh). EET-A administration prevented HF diet induced mitochondrial and dysfunction in adipose tissue and restored VO2 effects that were abrogated in PGC-1α-deficient mice. Conclusion. EET is identified as an upstream positive regulator of PGC-1α that leads to increased HO-1, decreased BW and fasting blood glucose and increased insulin receptor phosphorylation, that is, increased insulin sensitivity and mitochondrial integrity, and possible use of EET-agonist for treatment of obesity and metabolic syndrome.

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“…Additionally, we report that CYP2C44 levels were markedly decreased by HO-1 ablation, an effect that was reversed and normalized by increased adipocyte-specific levels of HO-1. This is of significance because the reduced expression of CYP2C44 leads to the reduced conversion of arachidonic acid into EETs, a detrimental blow to mitochondrial biogenesis, as EETs promote mitochondrial biogenesis [50].…”

Section: Discussionmentioning

confidence: 99%

Adipocyte Specific HO-1 Gene Therapy Is Effective in Antioxidant Treatment of Insulin Resistance and Vascular Function in an Obese Mice Model

et al. 2020

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Obesity is a risk factor for vascular dysfunction and insulin resistance. The study aim was to demonstrate that adipocyte-specific HO-1 (heme oxygenase-1) gene therapy is a therapeutic approach for preventing the development of obesity-induced metabolic disease in an obese-mice model. Specific expression of HO-1 in adipose tissue was achieved by using a lentiviral vector expressing HO-1 under the control of the adiponectin vector (Lnv-adipo-HO-1). Mice fed a high-fat diet (HFD) developed adipocyte hypertrophy, fibrosis, decreased mitochondrial respiration, increased levels of inflammatory adipokines, insulin resistance, vascular dysfunction, and impaired heart mitochondrial signaling. These detrimental effects were prevented by the selective expression of HO-1 in adipocytes. Lnv-adipo-HO-1-transfected mice on a HFD display increased cellular respiration, increased oxygen consumption, increased mitochondrial function, and decreased adipocyte size. Moreover, RNA arrays confirmed that targeting adipocytes with HO-1 overrides the genetic susceptibility of adiposopathy and correlated with restoration of the expression of anti-inflammatory, thermogenic, and mitochondrial genes. Our data demonstrate that HO-1 gene therapy improved adipose tissue function and had positive impact on distal organs, suggesting that specific targeting of HO-1 gene therapy is an attractive therapeutic approach for improving insulin sensitivity, metabolic activity, and vascular function in obesity.

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14,15-EET promotes mitochondrial biogenesis and protects cortical neurons against oxygen/glucose deprivation-induced apoptosis

Cited by 37 publications

References 27 publications

PGC-1 alpha regulates HO-1 expression, mitochondrial dynamics and biogenesis: Role of epoxyeicosatrienoic acid

PGC-1 alpha regulates HO-1 expression, mitochondrial dynamics and biogenesis: Role of epoxyeicosatrienoic acid

Downregulation of PGC-1αPrevents the Beneficial Effect of EET-Heme Oxygenase-1 on Mitochondrial Integrity and Associated Metabolic Function in Obese Mice

Adipocyte Specific HO-1 Gene Therapy Is Effective in Antioxidant Treatment of Insulin Resistance and Vascular Function in an Obese Mice Model

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