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Worldwide epidemics of metabolic diseases, including liver steatosis, are associated with an increased frequency of malignancies, showing the highest positive correlation for liver cancer. The heterogeneity of liver cancer represents a clinical challenge. In liver, the transcription factor PPAR[gamma] promotes metabolic adaptations of lipogenesis and aerobic glycolysis under the control of Akt2 activity, but the role of PPAR[gamma] in liver tumorigenesis is unknown. Here we have combined preclinical mouse models of liver cancer and genetic studies of a human liver biopsy atlas with the aim of identifying putative therapeutic targets in the context of liver steatosis and cancer. We have revealed a protumoral interaction of Akt2 signaling with hepatocyte nuclear factor 1[alpha] (HNF1[alpha]) and PPAR[gamma], transcription factors that are master regulators of hepatocyte and adipocyte differentiation, respectively. Akt2 phosphorylates and inhibits HNF1[alpha], thus relievingthe suppression of hepatic PPAR[gamma] expression and promoting tumorigenesis. Finally, we observed that pharmacological inhibition of PPAR[gamma] is therapeutically effective in a preclinical murine model of steatosis-associated liver cancer. Taken together, our studies in humans and mice reveal that Akt2 controls hepatic tumorigenesis through crosstalk between HNF1[alpha] and PPAR[gamma]., Introduction Hepatocellular carcinoma is the third leading cancer-related cause of death worldwide. This is partly due to late diagnosis and the fact that no efficient treatment is available. Recently, in [...]

Mitochondria and peroxisomes execute some analogous, nonredundant functions including fatty acid oxidation and detoxification of reactive oxygen species, and, in response to select metabolic cues, undergo rapid remodeling and division. Although these organelles share some components of their division machinery, it is not known whether a common regulator coordinates their remodeling and biogenesis. Here we show that in response to thermogenic stimuli, peroxisomes in brown fat tissue (BAT) undergo selective remodeling and expand in number and demonstrate that ectopic expression of the transcriptional coactivator PGC-1[alpha] recapitulates these effects on the peroxisomal compartment, both in vitro and in vivo. Conversely, [beta]-adrenergic stimulation of PGC-1[[alpha].sup.-/-] cells results in blunted induction of peroxisomal gene expression. Surprisingly, PPAR[alpha] was not required for the induction of critical biogenesis factors, suggesting that PGC-1[alpha] orchestrates peroxisomal remodeling through a PPAR[alpha]-independent mechanism. Our data suggest that PGC-1[alpha] is critical to peroxisomal physiology, establishing a role for this factor as a fundamental orchestrator of cellular adaptation to energy demands. organelle biogenesis | adaptive thermogenesis | energy metabolism doi/ 10.1073/pnas.1009176107