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Series GSE132458 Query DataSets for GSE132458
Status Public on Jun 11, 2019
Title Effects of Peroxisome proliferator-γ coactivator-1α (PGC-1a) isoform over-expression +/- TNFalpha on hepatocyte gene expression
Organism Mus musculus
Experiment type Expression profiling by array
Summary PGC-1a is a transcriptional coactivator known to regulate a broad gene program of nutrient and mitochondrial metabolism. Many splice variants of this protein have been identified, but their functions were unknown. This experiment was designed to delineate the downstream targets of two different PGC-1alpha isoforms (PGC-1a1 and PGC-1a4) in hepatocytes, and to determine whether inflammatory signaling (via TNFR activation) modulated these targets
Liver is exposed to constantly changing metabolic and inflammatory environments. It must quickly sense and adapt to metabolic need while balancing resources required to protect itself from harmful inflammatory molecules. PGC-1α is a transcriptional coactivator that mediates cellular adaptation to diverse stimuli including inflammation. PGC-1α has a protective role against inflammation in several organs, including brain, heart, kidney, muscle, and liver. However, it is not known how hepatic PGC-1α integrates extracellular signals to mitigate inflammatory outcomes. PGC-1α exists as multiple, alternatively spliced variants whose expression is differentially regulated by different gene promoters. In human liver, we found that inflammatory conditions preferentially activated the alternative versus proximal PPARGC1A promoter. Gene expression analysis performed in primary mouse hepatocytes identified many shared and isoform-specific roles for PGC-1α variants during acute inflammation. PGC-1α1 primarily impacted gene programs of nutrient and mitochondrial metabolism, while TNFα treatment revealed that PGC-1α4 uniquely influenced several pathways related to innate immunity and cell death. Gain- and loss-of-function models showed that PGC-1α4 specifically attenuated apoptosis in response to TNFα or LPS, in contrast to PGC-1α1, which reduced expression of a wide inflammatory gene network. We conclude that PGC-1α variants have distinct, yet complimentary roles in hepatic responses to inflammation, with PGC-1α4 being an important mitigator of apoptosis.
Overall design Primary mouse hepatocytes (isolated from C57BL/6J mice) were infected with adenovirus expression PGC-1a1, PGC-1a4 or vector only control. All vectors express GFP from a separate ORF. 48 hours after infection, cells were treated with 2 ng/mL TNFalpha for 2 hours (or PBS vehicle). Cells were harvest and RNA isolated for expression analsis.
Contributor(s) Estall JL, Leveille M
Citation(s) 32180561
Submission date Jun 10, 2019
Last update date Mar 23, 2020
Contact name Jennifer Lynn Estall
Phone 514-987-5688
Organization name IRCM
Street address 110 avenue des Pins ouest
City Montreal
State/province Quebec
ZIP/Postal code H2W1R7
Country Canada
Platforms (1)
GPL1261 [Mouse430_2] Affymetrix Mouse Genome 430 2.0 Array
Samples (18)
GSM3866435 WtPH: Vector 1
GSM3866436 WtPH: Vector 2
GSM3866437 WtPH: Vector 3
BioProject PRJNA548127

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Supplementary file Size Download File type/resource
GSE132458_RAW.tar 81.9 Mb (http)(custom) TAR (of CEL, CHP)
Raw data provided as supplementary file
Processed data included within Sample table
Processed data provided as supplementary file

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