Hepatic glucose-6-phosphatase-α deficiency leads to metabolic reprogramming in glycogen storage disease type Ia.
Hepatic glucose-6-phosphatase-α deficiency leads to metabolic reprogramming in glycogen storage disease type Ia.
复制标题
DOI：
10.1016/j.bbrc.2018.03.083
复制
发表时间：
2018-04-15
影响因子：
3.1
通讯作者：
Chou JY
中科院分区：
文献类型：
--
作者：
Cho JH;Kim GY;Mansfield BC;Chou JY
Ia型糖原储存病是由葡萄糖-6-磷酸酶-α(G6Pase-α或G6PC)缺乏引起的，G6Pase-G6PC是内源性葡萄糖产生的关键酶。这种常染色体隐性遗传病的特征是糖平衡受损和肝细胞腺瘤/癌(HCA/HCC)的长期并发症。我们已经证明，肝脏G6Pase-α缺陷介导的脂肪变性会导致自噬缺陷，而自噬缺陷往往与癌症的发生有关。我们现在发现，肝脏G6Pase-α缺乏也会导致肝脏糖酵解和己糖一磷酸分流的增强，这可能有助于肝癌的发生。肝脏糖酵解的增强反映在乳酸蓄积增加，许多糖酵解酶的表达增加，以及刺激糖酵解的c-Myc表达增加。HMS的增加反映为葡萄糖-6-磷酸脱氢酶活性的增加以及NADPH和还原型谷胱甘肽的产生增加。我们先前已经证明，在G6Pase-α缺陷的肝脏中恢复G6Pase-α的表达可以纠正代谢异常，使自噬正常化，并防止GSD-Ia中肝细胞癌/肝癌的发展。我们现在发现，恢复肝脏G6Pase-α的表达可以使糖酵解和糖代谢正常化。此外，在L-G6pc−/−小鼠的肝细胞癌/肝细胞癌病灶中，己糖激酶2(HK2)和丙酮酸激酶M2亚型(PKM2)水平升高，这在有氧糖酵解和癌细胞增殖中发挥重要作用。总之，肝脏G6Pase-α缺陷导致代谢重编程，导致糖酵解增强和Hms升高，与自噬受损一起可能有助于GSD-Ia中肝细胞癌/肝细胞癌的发展。
Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in glucose-6-phosphatase-α (G6Pase-α or G6PC), a key enzyme in endogenous glucose production. This autosomal recessive disorder is characterized by impaired glucose homeostasis and long-term complications of hepatocellular adenoma/carcinoma (HCA/HCC). We have shown that hepatic G6Pase-α deficiency-mediated steatosis leads to defective autophagy that is frequently associated with carcinogenesis. We now show that hepatic G6Pase-α deficiency also leads to enhancement of hepatic glycolysis and hexose monophosphate shunt (HMS) that can contribute to hepatocarcinogenesis. The enhanced hepatic glycolysis is reflected by increased lactate accumulation, increased expression of many glycolytic enzymes, and elevated expression of c-Myc that stimulates glycolysis. The increased HMS is reflected by increased glucose-6-phosphate dehydrogenase activity and elevated production of NADPH and the reduced glutathione. We have previously shown that restoration of hepatic G6Pase-α expression in G6Pase-α-deficient liver corrects metabolic abnormalities, normalizes autophagy, and prevents HCA/HCC development in GSD-Ia. We now show that restoration of hepatic G6Pase-α expression normalizes both glycolysis and HMS in GSD-Ia. Moreover, the HCA/HCC lesions in L-G6pc−/− mice exhibit elevated levels of hexokinase 2 (HK2) and the M2 isoform of pyruvate kinase (PKM2) which play an important role in aerobic glycolysis and cancer cell proliferation. Taken together, hepatic G6Pase-α deficiency causes metabolic reprogramming, leading to enhanced glycolysis and elevated HMS that along with impaired autophagy can contribute to HCA/HCC development in GSD-Ia.
登录
查看更多内容
影响因子：
13.8
作者：
Patra, Krushna C.;Hay, Nissim
通讯作者：
Hay, Nissim
I 型糖原累积病和 G6Pase-β 缺乏症：病因学和治疗。
DOI：
10.1038/nrendo.2010.189
发表时间：
2010-12
期刊：
Nature reviews. Endocrinology
影响因子：
--
作者：
通讯作者：
--
影响因子：
13.5
作者：
Lee, Young Mok;Jun, Hyun Sik;Pan, Chi-Jiunn;Lin, Su Ru;Wilson, Lane H.;Mansfield, Brian C.;Chou, Janice Y.
通讯作者：
Chou, Janice Y.
影响因子：
--
作者：
Traverso N;Ricciarelli R;Nitti M;Marengo B;Furfaro AL;Pronzato MA;Marinari UM;Domenicotti C
通讯作者：
Domenicotti C
影响因子：
11.5
作者：
Nogueira, Veronique;Hay, Nissim
通讯作者：
Hay, Nissim