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PGC-1α isoforms coordinate to balance hepatic metabolism and apoptosis in inflammatory environments

Mélissa Léveillé, Aurèle Besse-Patin, Nathalie Jouvet, Stewart Jeromson, Naveen P. Khan, Sarah Sczelecki, Cindy Baldwin, Annie Dumouchel, Jorge Correia, Paulo Jannig, Stephanie K. Petrillo, Anthoula Lazaris, Jonathan Boulais, Peter Metrakos, Jorge L. Ruas, View ORCID ProfileJennifer L. Estall
doi: https://doi.org/10.1101/703678
Mélissa Léveillé
1Institut de recherches cliniques de Montreal (IRCM), Montreal, Quebec, Canada
2Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
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Aurèle Besse-Patin
1Institut de recherches cliniques de Montreal (IRCM), Montreal, Quebec, Canada
2Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
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Nathalie Jouvet
1Institut de recherches cliniques de Montreal (IRCM), Montreal, Quebec, Canada
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Stewart Jeromson
1Institut de recherches cliniques de Montreal (IRCM), Montreal, Quebec, Canada
3Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
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Naveen P. Khan
1Institut de recherches cliniques de Montreal (IRCM), Montreal, Quebec, Canada
3Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
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Sarah Sczelecki
1Institut de recherches cliniques de Montreal (IRCM), Montreal, Quebec, Canada
3Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
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Cindy Baldwin
1Institut de recherches cliniques de Montreal (IRCM), Montreal, Quebec, Canada
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Annie Dumouchel
1Institut de recherches cliniques de Montreal (IRCM), Montreal, Quebec, Canada
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Jorge Correia
5Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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Paulo Jannig
5Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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Stephanie K. Petrillo
4Cancer Research Program, Department of Surgery, McGill University Health Center-Research Institute, Montreal, Quebec, H4A 3J1, Canada
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Anthoula Lazaris
4Cancer Research Program, Department of Surgery, McGill University Health Center-Research Institute, Montreal, Quebec, H4A 3J1, Canada
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Jonathan Boulais
1Institut de recherches cliniques de Montreal (IRCM), Montreal, Quebec, Canada
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Peter Metrakos
4Cancer Research Program, Department of Surgery, McGill University Health Center-Research Institute, Montreal, Quebec, H4A 3J1, Canada
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Jorge L. Ruas
5Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
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Jennifer L. Estall
1Institut de recherches cliniques de Montreal (IRCM), Montreal, Quebec, Canada
2Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
3Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
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  • ORCID record for Jennifer L. Estall
  • For correspondence: jennifer.estall@ircm.qc.ca
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ABSTRACT

Liver is exposed to changing metabolic and inflammatory environments. It must sense and adapt to metabolic need while balancing resources required to protect itself from insult. PGC-1α is a transcriptional coactivator that both coordinates metabolic adaptation to diverse stimuli and protects against inflammation in several tissues. However, it is not known how PGC-1α integrates extracellular signals to balance metabolic and anti-inflammatory outcomes. PGC-1α exists as multiple, alternatively spliced variants expressed from different promoters. We show in human liver, NALFD/NASH preferentially activated the alternative PPARGC1A promoter. Gene expression analysis in primary mouse hepatocytes identified shared and isoform-specific roles for PGC-1α variants in response to TNFα. PGC-1α1 primarily impacted gene programs of nutrient and mitochondrial metabolism, while TNFα signaling revealed that PGC-1α4 influenced several pathways related to innate immunity and cell death. Gain- and loss-of-function models showed that PGC-1α4 specifically enhanced expression of anti-apoptotic gene programs and attenuated hepatocyte apoptosis in response to TNFα or LPS. This was in contrast to PGC-1α1, which reduced expression of a wide inflammatory gene network, but did not prevent liver cell death. We conclude that PGC-1α variants have distinct, yet complimentary roles in hepatic responses to inflammation and identify PGC-1α4 as an important mitigator of apoptosis.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 16, 2019.
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PGC-1α isoforms coordinate to balance hepatic metabolism and apoptosis in inflammatory environments
Mélissa Léveillé, Aurèle Besse-Patin, Nathalie Jouvet, Stewart Jeromson, Naveen P. Khan, Sarah Sczelecki, Cindy Baldwin, Annie Dumouchel, Jorge Correia, Paulo Jannig, Stephanie K. Petrillo, Anthoula Lazaris, Jonathan Boulais, Peter Metrakos, Jorge L. Ruas, Jennifer L. Estall
bioRxiv 703678; doi: https://doi.org/10.1101/703678
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PGC-1α isoforms coordinate to balance hepatic metabolism and apoptosis in inflammatory environments
Mélissa Léveillé, Aurèle Besse-Patin, Nathalie Jouvet, Stewart Jeromson, Naveen P. Khan, Sarah Sczelecki, Cindy Baldwin, Annie Dumouchel, Jorge Correia, Paulo Jannig, Stephanie K. Petrillo, Anthoula Lazaris, Jonathan Boulais, Peter Metrakos, Jorge L. Ruas, Jennifer L. Estall
bioRxiv 703678; doi: https://doi.org/10.1101/703678

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