Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease.
Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease.
复制标题
DOI：
10.1038/ncomms9994
复制
发表时间：
2016-02-03
影响因子：
16.6
通讯作者：
Orešič M
中科院分区：
文献类型：
--
作者：
Hyötyläinen T;Jerby L;Petäjä EM;Mattila I;Jäntti S;Auvinen P;Gastaldelli A;Yki-Järvinen H;Ruppin E;Orešič M
非酒精性脂肪肝（NAFLD）是导致慢性肝病和2型糖尿病的主要危险因素。在这里，我们通过整合来自人类肝脏活检的全球转录组数据和在人类内脏血管床测量的代谢通量数据，在人类代谢的基因组规模模型内，绘制NAFLD中的肝脏代谢活性和功能。我们发现，肝脂肪的增加量诱导线粒体代谢，脂解，甘油生成和开关从乳酸甘油作为底物的代谢，表明一个复杂的平衡，加剧相反的代谢过程中血糖调节。这些变化与网络水平上的代谢适应性降低有关，因为肝脏脂肪积累对肝脏提出了越来越多的要求，以适应性地调节代谢反应，以维持基本的肝功能。我们认为，未能满足过度的代谢挑战加上代谢适应性降低可能会导致恶性致病循环，导致NAFLD的合并症。 非酒精性脂肪肝（NAFLD）是其他类型肝病的危险因素。在这里，作者将来自NAFLD患者的转录组学和代谢组学数据与基因组规模的代谢模型相结合，以描绘NAFLD患者肝功能的全面情况。
Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD. Non-alcoholic fatty liver disease (NAFLD) is a risk factor for other types of liver diseases. Here, the authors integrate transcriptomic and metabolomic data from patients with NAFLD with a genome-scale metabolic model to paint a comprehensive picture of liver function in NAFLD.