Abstract
Estrogen-related receptor α (ERRα) is a key regulator of mitochondrial function and metabolism essential for energy-driven cellular processes in both normal and cancer cells. ERRα has also been shown to mediate bone-derived macrophage activation by proinflammatory cytokines. However, the role of ERRα in cancer in which inflammation acts as a tumor promoter has yet to be investigated. Herein we show that global loss of ERRα accelerates the development of diethylnitrosamine (DEN)-induced hepatocellular carcinoma. Biochemical and metabolomics studies revealed that loss of ERRα promotes hepatocyte necrosis over apoptosis in response to DEN due to a deficiency in energy production. We further show that increased hepatocyte death and associated compensatory proliferation observed in DEN-injured ERRα-null livers is concomitant with increased nuclear factor κB (NF-κB)-dependent transcriptional control of cytokine expression in Kupffer cells. In particular, we demonstrate that loss of ERRα-dependent regulation of the NF-κB inhibitor IκBα leads to enhanced NF-κB activity and cytokine gene activation. Our work thus shows that global loss of ERRα activity promotes hepatocellular carcinoma by independent but synergistic mechanisms in hepatocytes and Kupffer cells, implying that pharmacological manipulation of ERRα activity may have a significant clinical impact on carcinogen-induced cancers.