PPARγ contributes to PKM2 and HK2 expression in fatty liver.
PPARγ contributes to PKM2 and HK2 expression in fatty liver.
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DOI：
10.1038/ncomms1667
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发表时间：
2012-02-14
影响因子：
16.6
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中科院分区：
文献类型：
--
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快速增殖的细胞在有氧条件下促进糖酵解，以增加生长速度。特定糖酵解酶的表达，即丙酮酸激酶M2和己糖激酶2，符合这种代谢适应，因为它们的动力学和细胞内定位有利于细胞增殖所需的生物合成过程。调节它们选择性表达的细胞内因子在很大程度上仍不清楚。在此，我们发现在PTEN缺失的脂肪肝中，过氧化物酶体增殖物激活受体、γ转录因子和核激素受体参与了选择性丙酮酸激酶M2和己糖激酶2基因的表达。在PTEN缺失的小鼠肝脏中，过氧化物酶体增殖物激活受体γ的表达、肝脏脂肪变性、向有氧糖酵解的转变以及肿瘤的发生都受到Akt2激酶的控制。过氧化物酶体增殖物激活受体γ与己糖激酶2和丙酮酸激酶M启动子结合，激活转录。体内挽救过氧化物酶体增殖物激活受体γ活性会导致肝脏脂肪变性、肥大和增生。我们的数据表明，胰岛素增敏剂和过氧化物酶体增殖物激活受体γ激动剂噻唑烷二酮类药物的治疗可能会产生相反的结果，这取决于肝脏脂肪变性的营养或遗传来源。调节有利于生物合成过程的特定糖酵解酶表达的分子因素仍然未知。Panasyuk等人。鉴定PPARγ是一种新的转录因子，启动丙酮酸激酶M2和己糖激酶2，这两种蛋白在病理生理生长中经常上调。
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. Molecular factors, regulating the expression of specific glycolytic enzymes that favour biosynthetic processes, have remained unknown. Panasyuk et al. identify PPARγ as a novel transcription factor turning on pyruvate kinase M2 and hexokinase 2, which are frequently upregulated in pathophysiological growth.
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