PGC-1α isoforms coordinate to balance hepatic metabolism and apoptosis in inflammatory environments
| العنوان: | PGC-1α isoforms coordinate to balance hepatic metabolism and apoptosis in inflammatory environments |
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| المؤلفون: | Sarah Sczelecki, Nathalie Jouvet, Mélissa Léveillé, Stewart Jeromson, Peter Metrakos, Aurèle Besse-Patin, Jorge C. Correia, Jorge L. Ruas, Jonathan Boulais, Annie Dumouchel, Stephanie Petrillo, Jennifer L. Estall, Naveen Khan, Anthoula Lazaris, Cindy Baldwin, Paulo R. Jannig |
| المصدر: | Molecular Metabolism Molecular Metabolism, Vol 34, Iss, Pp 72-84 (2020) |
| بيانات النشر: | Elsevier, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, Peroxisome proliferator-activated receptor, Apoptosis, Mice, 0302 clinical medicine, Gene expression, Protein Isoforms, chemistry.chemical_classification, Mice, Knockout, 0303 health sciences, Liver cell, PGC-1 isoforms, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, 3. Good health, Cell biology, Liver, Tumor necrosis factor alpha, Female, Original Article, PPARGC1A, tumor necrosis factor alpha, TNFα, medicine.symptom, Gene isoform, lcsh:Internal medicine, Programmed cell death, 030209 endocrinology & metabolism, Inflammation, Peroxisome proliferator activated receptor gamma coactivator-1 alpha, PGC-1α, PPARGC1A, Biology, Cell Line, 03 medical and health sciences, medicine, Animals, lcsh:RC31-1245, Molecular Biology, 030304 developmental biology, Innate immune system, urogenital system, Microarray analysis techniques, nuclear factor of kappa-light-chain-enhancer of activated B cells, NF-κB, Cell Biology, Mice, Inbred C57BL, 030104 developmental biology, Metabolism, chemistry, lipopolysaccharide, LPS, Hepatocytes, 030217 neurology & neurosurgery |
| الوصف: | Objective The liver is regularly exposed to changing metabolic and inflammatory environments. It must sense and adapt to metabolic need while balancing resources required to protect itself from insult. Peroxisome proliferator activated receptor gamma coactivator-1 alpha (PGC-1α) is a transcriptional coactivator expressed as multiple, alternatively spliced variants transcribed from different promoters that coordinate metabolic adaptation and protect against inflammation. It is not known how PGC-1α integrates extracellular signals to balance metabolic and anti-inflammatory outcomes. Methods Primary mouse hepatocytes were used to evaluate the role(s) of different PGC-1α proteins in regulating hepatic metabolism and inflammatory signaling downstream of tumor necrosis factor alpha (TNFα). Gene expression and signaling analysis were combined with biochemical measurement of apoptosis using gain- and loss-of-function in vitro and in vivo. Results Hepatocytes expressed multiple isoforms of PGC-1α, including PGC-1α4, which microarray analysis showed had common and isoform-specific functions linked to metabolism and inflammation compared with canonical PGC-1α1. Whereas PGC-1α1 primarily impacted gene programs of nutrient metabolism and mitochondrial biology, TNFα signaling showed several pathways related to innate immunity and cell death downstream of PGC-1α4. Gain- and loss-of-function models illustrated that PGC-1α4 uniquely enhanced expression of anti-apoptotic gene programs and attenuated hepatocyte apoptosis in response to TNFα or lipopolysaccharide (LPS). This was in contrast to PGC-1α1, which decreased the expression of a wide inflammatory gene network but did not prevent hepatocyte death in response to cytokines. Conclusions PGC-1α variants have distinct, yet complementary roles in hepatic responses to metabolism and inflammation, and we identify PGC-1α4 as an important mitigator of apoptosis. Graphical abstract Image 1 Highlights • Multiple isoforms of PGC-1α are expressed in hepatocytes, including PGC-1α4. • PGC-1α1 and PGC-1α4 share many metabolic targets, but PGC-1α4 has unique functions linked to hepatic inflammatory signalling. • PGC-1α4 attenuates hepatocyte apoptosis in response to TNFα and LPS in vitro and in vivo. • Inflammatory signaling influences PGC-1α4 localization in hepatocytes. |
| اللغة: | English |
| تدمد: | 2212-8778 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::c72c5a385cc6091aa8b794d8d30681f6 http://europepmc.org/articles/PMC7011010 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....c72c5a385cc6091aa8b794d8d30681f6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22128778 |
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