New player in the aerobic glycolysis and liver tumorigenesis – unexplored role of PPARg

Growth is a fundamental process defined as accumulation of mass and is tightly controlled by nutrient availability. Overnutrition may lead to obesity, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease and cancer. In order to increase growth rate rapidly proliferating cells promote glycolysis in aerobic conditions. Expression of specific glycolytic enzymes, namely pyruvate kinase M2 (PKM2) and hexokinase 2 (HK2), concurs to this metabolic adaptation, as their kinetics and intracellular localization favour biosynthetic processes required for cell proliferation. Intracellular factors regulating their selective expression remain largely unknown. Using mouse model of hepatocytes specific PTEN deletion which is prone to steatosis and liver cancer we revealed that the PPARγ transcription factor and nuclear hormone receptor is a potent and selective activator of PKM2 and HK2 gene expression versus the other glycolytic genes. We discovered that PPARγ expression, liver steatosis, shift to aerobic glycolysis and tumorigenesis are under the control of the Akt2 kinase in PTEN-null mouse livers. PPARγ directly binds the promoters of HK2 and PKM to activate transcription. In vivo rescue of PPARγ activity in PTEN;Akt2 deficient mice causes liver steatosis, hypertrophy and hyperplasia accompanied by increased selective expression of PKM2 and HK2 with no effect on other glycolytic enzymes including PKL, enolase or GAPDH. Furthermore the growth promoting action of PPARγ in liver was dependent on glycolysis as treatment of PPARγ-transduced mice with the glycolytic inhibitor 3-bromopyruvate (3-BrPA) inhibited liver growth. Conversely, genetic deletion of PPARγ in PTEN-null mice rescued the steatosis and liver hypertrophy. Our data imply that therapies with the insulin-sensitizing agents and PPARγ agonists thiazolidinediones, may have opposite outcomes depending on the nutritional or genetic origins of liver steatosis. Consistently, chronic activation of PPARγ in PTEN-null mice led to acceleration of hepatic tumorigenesis. Furthermore, we have observed that substantial fraction of human hepatocellular carcinomas display elevated levels of PPARγ, PKM2 and HK2 which is inversely correlated with PTEN levels. In sum, we propose that PPARγ plays an unrecognised role in pathological liver growth and could represent a potential new therapeutic target for treatment of liver cancer.