Loss Of Estrogen-Related Receptor A Promotes Hepatocarcinogenesis Development Via Metabolic And Inflammatory Disturbances

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