PPARγ contributes to PKM2 and HK2 expression in fatty liver

Abstract

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-null 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-null 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.

Splicing regulator SLU7 is essential for maintaining liver homeostasis

“…We demonstrated that Slu7 downregulation resulted in significantly increased hepatic glucose uptake and catabolism, as demonstrated by intrahepatic lactate concentrations ( Figure 6, B-D). The forced expression of PKM2 and HK2 activates hepatocellular growth in normal liver (39). We found that the cell cycle-related genes Foxm1, Nor1, and early growth response 1 (Egr1) and the cyclins Ccnd1, Ccna2, and Ccnb2 were all upregulated in Slu7-depleted mouse livers and in SLU7-silenced HepG2 cells ( Figure 7A and Supplemental Figure 6).…”

“…Slu7 knockdown resulted in downregulation of Mat1a, glutaminase 2 (Gls2), glucokinase (Gck), and L-pyruvate kinase (Lpk) and concomitant upregulation of Mat2a, Gls1, hexokinase 2 (Hk2), and pyruvate kinase m2 (Pkm2), together with a switch in the expression of Hnf4α isoforms derived from the P1 and P2 gene promoters and in the ratio of Insr A and B splice variants ( Figure 3E and Supplemental Figure 2). The isozymes, Hnf4α P2-derived isoforms, and splice variants favored upon Slu7 downregulation were characteristic of the fetal and/or transformed hepatocyte, which exert profound effects on metabolism (26,30,(36)(37)(38)(39)(40).…”

Oxidative stress promotes pathologic polyploidization in nonalcoholic fatty liver disease

“…We first evaluated the nuclear ploidy profile in 3-month-old Pten KO mice at pretumoral stages. At this age, the Pten KO mouse liver shows extensive steatohepatitis (51,52). Similar to other NAFLD models, the ploidy profile of Pten KO livers was different from that of WT livers and was characterized by the amplification of the highly polyploid mononuclear population (Supplemental Figure 2A and Table 2).…”

“…Lanes were run on the same gel but were noncontiguous. (52). For investigations with the antioxidant NAC, heterozygous male and female ob/+ mice were mated and had a free access to water with or without 10 mM NAC.…”

“…In order to establish a relationship between hepatocyte polyploidy and HCC incidence, we have also analyzed ploidy profile in 10-month-old Pten KO mice. At this age, hepatic PTEN mutants are presented with multiple malignant lesions (51,52). Importantly, we observed that highly polyploid mononuclear hepatocytes (≥8n) were also enriched in livers of tumoral KO mice compared with those in control animals spectrum of hepatic lesions, ranging from simple reversible steatosis (intrahepatic accumulation of triglycerides) and nonalcoholic steatohepatitis (NASH) to more severe lesions, such as cirrhosis and hepatocellular carcinoma (HCC) (23)(24)(25).…”