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.
