Hepatic peroxisome proliferator-activated receptor coactivator 1 drives mitochondrial and anabolic signatures that contribute to hepatocellular carcinoma progression in mice

The peroxisome proliferator-activated receptor (PPAR) coactivator-1 (PGC-1 ) is a master regulator of mitochondrial biogenesis and oxidative metabolism as well as of antioxidant defense. Specifically, in the liver, PGC-1 also promotes de novo lipogenesis, thus sustaining cellular anabolic processes. Given the relevant pathogenic role of mitochondrial and fatty acid metabolism in hepatocarcinoma (HCC), here we pointed to PGC-1 as a putative novel transcriptional player in the development and progression of HCC. For this purpose, we generated both hepatic-specific PGC-1-overexpressing (LivPGC-1) and PGC-1 knockout (LivPGC-1KO) mice, and we challenged them with both chemical and genetic models of hepatic carcinogenesis. Our results demonstrate a pivotal role of PGC-1 in driving liver tumor development. Indeed, whereas mice overexpressing PGC-1 show greater tumor susceptibility, PGC-1 knockout mice are protected from carcinogenesis. High levels of PGC-1 are able to boost reactive oxygen species (ROS) scavenger expression, therefore limiting the detrimental ROS accumulation and, consequently, apoptosis. Moreover, it supports tumor anabolism, enhancing the expression of genes involved in fatty acid and triglyceride synthesis. Accordingly, the specific hepatic ablation of PGC-1 promotes the accumulation of ROS-driven macromolecule damage, finally limiting tumor growth. Conclusion: The present data elect hepatic PGC-1 as a transcriptional gatekeeper of mitochondrial function and redox status in HCC, orchestrating different metabolic programs that allow tumor progression. (Hepatology 2018;67:884-898)