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

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• 作者：Shailendra P. Singh^a ; ¹ ; Joseph Schragenheim^a ; ¹ ; Jian Cao^c ; John R. Falck^d ; Nader G. Abraham^a ; ^b ; ^e ; ^{Nader_Abraham@nymc.edu" class="auth_mail" title="E-mail the corresponding author} ; Lars Bellner^a ; ^{Lars_bellner@nymc.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：BACH1 ; BTB and CNC homology 1 basic leucine zipper transcription factor 1 ; CO ; carbon monoxide ; COX-IV ; cytochrome C oxidase subunit IV ; DM2 ; diabetes mellitus type 2 ; EET ; epoxyeiocosatrienoic acid ; EET-A ; EET agonist ; GAPDH ; glyceraldehyde-3-phosphate dehydrogenase ; HO ; heme oxygenase ; Mfn ; mitofusin ; MnSOD/SOD2 ; manganese-containing superoxide dismutase/superoxide dismutase 2 mitochondrial ; OPA1 ; optic atrophy 1 (autosomal dominant) ; PEG1/MEST ; paternally-expressed gene 1 protein/mesoderm spe
• 刊名：Prostaglandins and Other Lipid Mediators
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：125
• 期：Complete
• 页码：8-18
• 全文大小：2321 K

文摘

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.

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.