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

Abstract

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.

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

“…EET-mediated induction of PGC-1 α and HO-1 favors an increase in mitochondrial fusion, biogenesis, and OXPHOS, thereby providing metabolic protection in HF diet induced obesity in mice; this finding is supported by recent reports by us and others showing that HO-1 regulates mitochondrial function, quality control, biogenesis, and dynamics [46, 57, 58]. …”

Ablation of adipose-HO-1 expression increases white fat over beige fat through inhibition of mitochondrial fusion and of PGC1α in female mice

“…Concomitantly inhibition of HO activity reduces mitochondrial quality control by inhibition of mitochondrial fusion mediator Mfn1, Mfn2 and Opa1 but activation of mitochondrial fission mediator Fis1 [42], [43]. Hence, our study offers a portal on the unique role of HO-1 in adipose tissue by its ability to maintain mitochondrial quality and biogenesis.…”

“…Mice were divided into two groups (n = 6 per group): adipo-HO-1 +/+ and adipo-HO-1 −/− lenti-aP2-HO-1 at 30 weeks of age. Mice were weighed every week, blood glucose was determined [16], [18], [42]. All experimental protocols were performed follow- …”

“…Specific TaqMan ® Gene Expression Assays probes for mouse HO-1, PGC1α, COX-IV (cytochrome c oxidase subunit-IV), adiponectin, TNFα, and other signaling RNA were determined as previously described [42], [43].…”

Irisin Regulates Heme Oxygenase-1/Adiponectin Axis in Perivascular Adipose Tissue and Improves Endothelial Dysfunction in Diet-Induced Obese Mice

“…And this further increased browning genes in PVAT from HFD mice, which shift the PVAT from white to brown characteristics. Browning of PVAT may upregulate HO-1 by PGC1α and secret more protective cytokines such as adiponectin and less proinflammatory cytokines and, thus, may have a net beneficial effect on endothelial function [35]. …”