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

Abstract

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. PGC-1 is a transcriptional coactivator that both coordinates metabolic adaptation to diverse stimuli and protects against inflammation. However, it is not known how PGC-1 integrates extracellular signals to balance metabolic and anti-inflammatory outcomes. PGC-1 exists as multiple, alternatively spliced variants expressed from different promoters. Primary mouse hepatocytes were used to evaluate the role(s) of different PGC-1 proteins in regulating hepatic metabolism and inflammatory signaling downstream of TNF. PGC-11 and PGC-14 were expressed in hepatocytes and expression analysis uncovered shared and isoform-specific roles for these variants linked to metabolism and inflammation. PGC-11 primarily impacted gene programs of nutrient and mitochondrial metabolism, while TNF signaling revealed that PGC-14 influenced several pathways related to innate immunity and cell death. Gain- and loss-of-function models illustrated that PGC-14 uniquely enhanced expression of anti-apoptotic gene programs and attenuated hepatocyte apoptosis in response to TNF or LPS. This was in contrast to PGC-11, which reduced the expression of a wide inflammatory gene network, but did not prevent liver cell death in response to the cytokine. We conclude that PGC-1 variants have distinct, yet complimentary roles in hepatic responses to metabolism and inflammation and identify PGC-14 as an important mitigator of apoptosis.