PT  - JOURNAL ARTICLE
AU  - Léveillé, Mélissa
AU  - Besse-Patin, Aurèle
AU  - Jouvet, Nathalie
AU  - Jeromson, Stewart
AU  - Khan, Naveen P.
AU  - Sczelecki, Sarah
AU  - Baldwin, Cindy
AU  - Dumouchel, Annie
AU  - Correia, Jorge
AU  - Jannig, Paulo
AU  - Petrillo, Stephanie K.
AU  - Lazaris, Anthoula
AU  - Boulais, Jonathan
AU  - Metrakos, Peter
AU  - Ruas, Jorge L.
AU  - Estall, Jennifer L.
TI  - PGC-1α isoforms coordinate to balance hepatic metabolism and apoptosis in inflammatory environments
AID  - 10.1101/703678
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 703678
4099  - http://biorxiv.org/content/early/2019/07/16/703678.short
4100  - http://biorxiv.org/content/early/2019/07/16/703678.full
AB  - 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.