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

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-1 alpha) 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-1 alpha integrates extracellular signals to balance metabolic and antiinflammatory outcomes. Methods: Primary mouse hepatocytes were used to evaluate the role(s) of different PGC-1 alpha proteins in regulating hepatic metabolism and inflammatory signaling downstream of tumor necrosis factor alpha (TNF alpha). 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-1 alpha, including PGC-1 alpha 4, which microarray analysis showed had common and isoform-specific functions linked to metabolism and inflammation compared with canonical PGC-1 alpha 1. Whereas PGC-1 alpha 1 primarily impacted gene programs of nutrient metabolism and mitochondrial biology, TNF alpha signaling showed several pathways related to innate immunity and cell death downstream of PGC-1 alpha 4. Gain- and loss-of-function models illustrated that PGC-1 alpha 4 uniquely enhanced expression of anti-apoptotic gene programs and attenuated hepatocyte apoptosis in response to TNF alpha or lipopolysaccharide (LPS). This was in contrast to PGC-1 alpha 1, which decreased the expression of a wide inflammatory gene network but did not prevent hepatocyte death in response to cytokines. Conclusions: PGC-1 alpha variants have distinct, yet complementary roles in hepatic responses to metabolism and inflammation, and we identify PGC-1 alpha 4 as an important mitigator of apoptosis. (C) 2020 The Author(s). Published by Elsevier GmbH.