PPARγ contributes to PKM2 and HK2 expression in fatty liver.
Bottom Line: Rapidly proliferating cells promote glycolysis in aerobic conditions, to increase growth rate.Intracellular factors regulating their selective expression remain largely unknown.Our data suggest that therapies with the insulin-sensitizing agents and peroxisome proliferator-activated receptor gamma agonists, thiazolidinediones, may have opposite outcomes depending on the nutritional or genetic origins of liver steatosis.
Affiliation: Inserm, U845, Paris 75015, France.
Rapidly proliferating cells promote glycolysis in aerobic conditions, to increase growth rate. Expression of specific glycolytic enzymes, namely pyruvate kinase M2 and hexokinase 2, 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. Here we show that the peroxisome proliferator-activated receptor gamma transcription factor and nuclear hormone receptor contributes to selective pyruvate kinase M2 and hexokinase 2 gene expression in PTEN- fatty liver. Peroxisome proliferator-activated receptor gamma expression, liver steatosis, shift to aerobic glycolysis and tumorigenesis are under the control of the Akt2 kinase in PTEN- mouse livers. Peroxisome proliferator-activated receptor gamma binds to hexokinase 2 and pyruvate kinase M promoters to activate transcription. In vivo rescue of peroxisome proliferator-activated receptor gamma activity causes liver steatosis, hypertrophy and hyperplasia. Our data suggest that therapies with the insulin-sensitizing agents and peroxisome proliferator-activated receptor gamma agonists, thiazolidinediones, may have opposite outcomes depending on the nutritional or genetic origins of liver steatosis.
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Mentions: Consistent with the positive role of the PI3K pathway on the cell switch to glycolytic metabolism2, PTEN- mouse livers showed a global upregulation of glycolytic enzymes (Fig. 1). The expression of multiple glycolytic enzymes that are commonly expressed in liver, including glucokinase (GCK), glucose phosphate isomerase 1 (GPI1), glyceraldehyde 3-phosphate dehydrogenase (GAPDH), enolase 1 (ENO1), phosphoglycerate kinase 1 (PGK1) and L-type pyruvate kinase (PKL) was augmented at the messenger RNA and protein levels (Fig. 1a,b). The increase in expression paralleled increased enzymatic activity, while mitochondrial enzymes such as citrate synthase and cytochrome c oxydase were not affected (Supplementary Fig. S1). These metabolic changes were concomitant with liver triglyceride accumulation (steatosis) and hyperplasia, hypoglycaemia and insulin hypersensitivity, and preceded the adenocarcinoma formation that was observed since 7 months of age1415 (Supplementary Fig. S2). As Akt2 has a crucial role mediating the action of insulin and PI3K on hepatic glucose homeostasis, steatosis, hyperplasia and tumorigenesis161719 (Supplementary Fig. S2), we addressed the effect of Akt2 deletion on glycolysis of PTEN- livers. Surprisingly, the upregulation of all the above mentioned glycolytic enzymes was also observed in AlbCre;PTENf/f;Akt2−/− livers (Fig. 1a,b; Supplementary Fig. S1), ruling out an involvement of Akt2 in this general activation of glycolysis.