Overexpression of PGC-1α increases peroxisomal activity and mitochondrial fatty acid oxidation in human primary myotubes

Huang, Tai‐Yu; Zheng, Donghai; Houmard, Joseph A.; Brault, Jeffrey J.; Hickner, Robert C.; Cortright, Ronald N.

doi:10.1152/ajpendo.00331.2016

Cited by 69 publications

(65 citation statements)

References 58 publications

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“…Moreover, mitochondria and peroxisomes also share transcription factors for their biogenesis. The observed cooperative expressions of mitochondrial and peroxisomal proteins by PPAR activators (fibrates) or by over‐expression of PGC‐1 α further confirms the biogenetic link between mitochondria and peroxisomes. Therefore, for efficient protection against inflammatory damage to myelin and axons, functional and structural protection of mitochondria and peroxisomes and myelin/axons are important.…”

Section: Discussionsupporting

confidence: 55%

Combination therapy of lovastatin and AMP‐activated protein kinase activator improves mitochondrial and peroxisomal functions and clinical disease in experimental autoimmune encephalomyelitis model

et al. 2018

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Recent studies report that loss and dysfunction of mitochondria and peroxisomes contribute to the myelin and axonal damage in multiple sclerosis (MS). In this study, we investigated the efficacy of a combination of lovastatin and AMP-activated protein kinase (AMPK) activator (AICAR) on the loss and dysfunction of mitochondria and peroxisomes and myelin and axonal damage in spinal cords, relative to the clinical disease symptoms, using a mouse model of experimental autoimmune encephalomyelitis (EAE, a model for MS). We observed that lovastatin and AICAR treatments individually provided partial protection of mitochondria/peroxisomes and myelin/axons, and therefore partial attenuation of clinical disease in EAE mice. However, treatment of EAE mice with the lovastatin and AICAR combination provided greater protection of mitochondria/peroxisomes and myelin/axons, and greater improvement in clinical disease compared with individual drug treatments. In spinal cords of EAE mice, lovastatin-mediated inhibition of RhoA and AICAR-mediated activation of AMPK cooperatively enhanced the expression of the transcription factors and regulators (e.g. PPARα/β, SIRT-1, NRF-1, and TFAM) required for biogenesis and the functions of mitochondria (e.g. OXPHOS, MnSOD) and peroxisomes (e.g. PMP70 and catalase). In summary, these studies document that oral medication with a combination of lovastatin and AICAR, which are individually known to have immunomodulatory effects, provides potent protection and repair of inflammation-induced loss and dysfunction of mitochondria and peroxisomes as well as myelin and axonal abnormalities in EAE. As statins are known to provide protection in progressive MS (Phase II study), these studies support that supplementation statin treatment with an AMPK activator may provide greater efficacy against MS.

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Section: Discussionsupporting

confidence: 55%

Combination therapy of lovastatin and AMP‐activated protein kinase activator improves mitochondrial and peroxisomal functions and clinical disease in experimental autoimmune encephalomyelitis model

et al. 2018

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“…In our in vitro system, we observed an inducing effect of EPO on genes previously known to play a role in myelination, such as Igf1, Igf2 , and Ptpre , as well as genes involved in lipid transport and metabolism, including Fat/Cd36, Ppargc1a/Pgc1alpha , and Pnlip ( 18 – 24 ).…”

Section: Discussionmentioning

confidence: 74%

“…To this purpose, we analyzed the changes in the gene expression profile induced by EPO in differentiating cells at two time points, 1 and 20 h after EPO treatment, focusing on the transcriptional changes occurring during the OPC to OL transition. The results highlight an inducing effect of EPO on genes previously known to play a role in myelination, such as insulin-like growth factor-1 ( Igf1 ), Igf2 , protein tyrosine phosphatase receptor type E ( Ptpre ), as well as genes involved in lipid transport and metabolism, including fatty acid translocase ( Fat/Cd36 ), peroxisome proliferator-activated receptor-gamma coactivator ( Ppargc1a / Pgc1alpha ), and pancreatic lipase ( Pnlip ) ( 18 – 24 ).…”

Section: Introductionmentioning

confidence: 97%

Erythropoietin Increases Myelination in Oligodendrocytes: Gene Expression Profiling Reveals Early Induction of Genes Involved in Lipid Transport and Metabolism

et al. 2017

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Several studies have shown that erythropoietin (EPO) has neuroprotective or neuroreparative actions on diseases of the nervous system and that improves oligodendrocyte (OL) differentiation and myelination in vivo and in vitro. This study aims at investigating the early molecular mechanisms for the pro-myelinating action of EPO at the gene expression level. For this purpose, we used a differentiating OL precursor cell line, rat central glia-4 cells. Cells were differentiated or not, and then treated with EPO for 1 or 20 h. RNA was extracted and changes in the gene expression profile were assessed using microarray analysis. Experiments were performed in biological replicates of n = 4. Differentiation alone changed the expression of 11% of transcripts (2,663 out of 24,272), representing 2,436 genes, half of which were upregulated and half downregulated. At 20 h of treatment, EPO significantly affected the expression of 99 genes that were already regulated by differentiation and of 150 genes that were not influenced by differentiation alone. Analysis of the transcripts most upregulated by EPO identified several genes involved in lipid transport (e.g., Cd36) and lipid metabolism (Ppargc1a/Pgc1alpha, Lpin1, Pnlip, Lpin2, Ppard, Plin2) along with Igf1 and Igf2, growth factors known for their pro-myelinating action. All these genes were only induced by EPO and not by differentiation alone, except for Pnlip which was highly induced by differentiation and augmented by EPO. Results were validated by quantitative PCR. These findings suggest that EPO might increase remyelination by inducing insulin-like growth factors and increasing lipid metabolism.

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“…Nevertheless, genes encoding enzymes involved in peroxisomal FAO, but also mitochondrial FAO, were strongly suppressed in M1 microglia, indicating that a common transcriptional regulator might be involved. We hypothesize that peroxisome proliferator-activated receptor gamma coactivator (PGC)1α could be such regulator, as it has already been proven that PGC1α controls the expression of enzymes of both mitochondrial and peroxisomal βoxidation [78]. Moreover, it has also been shown that BV-2 microglia downregulate PGC1α expression upon LPS stimulation and that its overexpression leads to reduced inflammatory responses of microglia upon LPS stimulation, favoring PGC1α as a potential regulator of M1 polarization [79].…”

Section: Discussionmentioning

confidence: 97%

Metabolic Reprogramming during Microglia Activation

et al. 2019

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Microglia, the specialized macrophages of the brain, can adopt different shapes and functions, some of which may be detrimental for nervous tissue. Similar to other immune cells, the metabolic program may determine the phenotypic features of microglia, and could constitute a therapeutic target in neurological diseases. Because the knowledge on microglial metabolism was sparse we here employed mouse primary microglia cells polarized into a pro- or anti-inflammatory state to define their metabolic features. After stimulation with either IL1β/IFNγ or IL4, the activity of glycolysis, glucose oxidation, glutamine oxidation, mitochondrial and peroxisomal fatty acid β-oxidation, and fatty acid synthesis, was assessed by using radiolabeled substrates. We complemented these data with transcriptome analysis of key enzymes orchestrating these metabolic pathways. Pro-inflammatory microglia exhibit increased glucose and glutamine metabolism and suppress both fatty acid oxidation and to a lesser extent fatty acid synthesis. On the other hand, anti-inflammatory microglia display changes only in fatty acid metabolism upregulating both fatty acid oxidation and fatty acid synthesis. Importantly, also human microglia-like cells differentiated from pluripotent stem cells upregulate glycolysis in pro-inflammatory conditions. Finally, we show that glycolytic enzymes are induced in a pro-inflammatory brain environment in vivo in mice. Taken together, the distinct metabolism in pro- and anti-inflammatory microglia can constitute a target to direct the microglial phenotype.

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Overexpression of PGC-1α increases peroxisomal activity and mitochondrial fatty acid oxidation in human primary myotubes

Cited by 69 publications

References 58 publications

Combination therapy of lovastatin and AMP‐activated protein kinase activator improves mitochondrial and peroxisomal functions and clinical disease in experimental autoimmune encephalomyelitis model

Combination therapy of lovastatin and AMP‐activated protein kinase activator improves mitochondrial and peroxisomal functions and clinical disease in experimental autoimmune encephalomyelitis model

Erythropoietin Increases Myelination in Oligodendrocytes: Gene Expression Profiling Reveals Early Induction of Genes Involved in Lipid Transport and Metabolism

Metabolic Reprogramming during Microglia Activation

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