Vaitheesvaran B, Hartil K, Navare A, OBroin P, Golden A, Lee Wn, Kurland I J, Bruce J E
Department of Medicine, Diabetes Center, Stable Isotope and Metabolomics Core Facility, Albert Einstein College of Medicine, Bronx, New York, 10461.
Department of Genome Sciences, University of Washington, Seattle, Washington, 98109.
Metabolomics. 2014 Oct 1;10(5):920-937. doi: 10.1007/s11306-014-0639-9.
Deficiency of IQGAP2, a scaffolding protein expressed primarily in liver leads to rearrangements of hepatic protein compartmentalization and altered regulation of enzyme functions predisposing development of hepatocellular carcinoma and diabetes. Employing a systems approach with proteomics, metabolomics and fluxes characterizations, we examined the effects of IQGAP2 deficient proteomic changes on cellular metabolism and the overall metabolic phenotype. mice demonstrated metabolic inflexibility, fasting hyperglycemia and obesity. Such phenotypic characteristics were associated with aberrant hepatic regulations of glycolysis/gluconeogenesis, glycogenolysis, lipid homeostasis and futile cycling corroborated with corresponding proteomic changes in cytosolic and mitochondrial compartments. IQGAP2 deficiency also led to truncated TCA-cycle, increased anaplerosis, increased supply of acetyl-CoA for lipogenesis, and increased mitochondrial methyl-donor metabolism necessary for nucleotides synthesis. Our results suggest that changes in metabolic networks in IQGAP2 deficiency create a hepatic environment of a 'pre-diabetic' phenotype and a predisposition to non-alcoholic fatty liver disease (NAFLD) which has been linked to the development of hepatocellular carcinoma.
IQGAP2是一种主要在肝脏中表达的支架蛋白，其缺乏会导致肝脏蛋白质区室化重排以及酶功能调节改变，从而易引发肝细胞癌和糖尿病。我们采用蛋白质组学、代谢组学和通量表征的系统方法，研究了IQGAP2缺乏引起的蛋白质组学变化对细胞代谢和整体代谢表型的影响。小鼠表现出代谢灵活性受损、空腹高血糖和肥胖。这些表型特征与糖酵解/糖异生、糖原分解、脂质稳态和无效循环的肝脏异常调节有关，同时伴有细胞质和线粒体区室中相应的蛋白质组学变化。IQGAP2缺乏还导致三羧酸循环缩短、回补反应增加、用于脂肪生成的乙酰辅酶A供应增加以及核苷酸合成所需的线粒体甲基供体代谢增加。我们的结果表明，IQGAP2缺乏时代谢网络的变化会形成一种“糖尿病前期”表型的肝脏环境，并易患非酒精性脂肪性肝病（NAFLD），而NAFLD与肝细胞癌的发生有关。
