title: 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.
authors.affiliation: Inserm, U845, Paris 75015, France.
authors.forename: Ganna
authors.initials: G
authors.lastname: Panasyuk
authors.forename: Catherine
authors.initials: C
authors.lastname: Espeillac
authors.forename: Céline
authors.initials: C
authors.lastname: Chauvin
authors.forename: Ludivine A
authors.initials: LA
authors.lastname: Pradelli
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Horie
authors.forename: Akira
authors.initials: A
authors.lastname: Suzuki
authors.forename: Jean-Sebastien
authors.initials: JS
authors.lastname: Annicotte
authors.forename: Lluis
authors.initials: L
authors.lastname: Fajas
authors.forename: Marc
authors.initials: M
authors.lastname: Foretz
authors.forename: Francisco
authors.initials: F
authors.lastname: Verdeguer
authors.forename: Marco
authors.initials: M
authors.lastname: Pontoglio
authors.forename: Pascal
authors.initials: P
authors.lastname: Ferré
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.forename: Jean-Ehrland
authors.initials: JE
authors.lastname: Ricci
authors.forename: Mario
authors.initials: M
authors.lastname: Pende
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis*; D049109:Cell Proliferation; D005234:Fatty Liver / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006019:Glycolysis; D006593:Hexokinase / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007328:Insulin / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D047495:PPAR gamma / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology; D013963:Thyroid Hormones / Q000096:biosynthesis*; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D006593:Hexokinase; D007328:Insulin; D008565:Membrane Proteins; D047495:PPAR gamma; D051057:Proto-Oncogene Proteins c-akt; D045162:Thiazolidinediones; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins