Metabolomic signatures in lipid-loaded HepaRGs reveal pathways involved in steatotic progression.
Metabolomic signatures in lipid-loaded HepaRGs reveal pathways involved in steatotic progression.
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DOI：
10.1002/oby.20440
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发表时间：
2013-12
期刊：
影响因子：
6.9
通讯作者：
Cheatham, Bentley
中科院分区：
文献类型：
--
作者：
Brown, Meredith V.;Compton, Sarah A.;Milburn, Michael V.;Lawton, Kay A.;Cheatham, Bentley
非酒精性脂肪肝病 (NAFLD) 描述了一系列疾病，包括单纯性脂肪变性、非酒精性脂肪性肝炎、纤维化和肝硬化。随着肥胖症以及随之而来的 NAFLD 患病率的增加，该领域需要新的治疗方法。为了促进这项工作，我们使用 HepaRG 细胞开发了肝脂肪变性的细胞模型，并确定了由此产生的生化变化。使用整体代谢组学分析，通过一种新颖的代谢物提取程序，我们检查了对饱和脂肪酸棕榈酸酯以及饱和和不饱和脂肪酸、棕榈酸酯和油酸酯的混合物（1:2）的代谢曲线。我们观察到，在采用棕榈酸酯和棕榈酸酯:油酸酯治疗的脂肪肝 HepaRG 模型中，支链氨基酸、TCA 循环中间体、鞘氨醇和酰基肉碱水平升高，而肉碱水平降低。此外，棕榈酸诱导的脂肪变性细胞选择性地表现出二酰甘油和单酰甘油水平升高，以及胆汁酸代谢改变。这种整体代谢组学方法揭示了在肝脂肪变性转变过程中重要途径的生化变化，包括胰岛素抵抗、线粒体代谢改变和氧化应激。此外，我们的数据证明了该体外模型在研究 NAFLD 脂肪变性进展、胰岛素抵抗和脂毒性机制方面的实用性。
Non-alcoholic fatty liver disease (NAFLD) describes a spectrum of disorders including simple steatosis, non-alcoholic steatohepatitis, fibrosis, and cirrhosis. With the increased prevalence of obesity, and consequently NAFLD, there is a need for novel therapeutics in this area. To facilitate this effort, we developed a cellular model of hepatic steatosis using HepaRG cells and determined the resulting biochemical alterations. Using global metabolomic profiling, by means of a novel metabolite extraction procedure, we examined the metabolic profiles in response to the saturated fatty acid palmitate, and a mixture of saturated and unsaturated fatty acids, palmitate and oleate (1:2). We observed elevated levels of the branched chain amino acids, TCA cycle intermediates, sphingosine and acylcarnitines, and reduced levels of carnitine in the steatotic HepaRG model with both palmitate and palmitate:oleate treatments. In addition, palmitate-induced steatotic cells selectively displayed elevated levels of diacylglycerols and monoacylglycerols, as well as altered bile acid metabolism. This global metabolomics approach reveals biochemical changes in pathways important in the transition to hepatic steatosis including insulin resistance, altered mitochondrial metabolism, and oxidative stress. Moreover, our data demonstrate the utility of this in vitro model for investigating mechanisms of steatotic progression, insulin resistance and lipotoxicity in NAFLD.
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非酒精性脂肪肝病的发病机理。
DOI：
10.1093/qjmed/hcp158
发表时间：
2010-02
期刊：
QJM : monthly journal of the Association of Physicians
影响因子：
--
作者：
Dowman JK;Tomlinson JW;Newsome PN
通讯作者：
Newsome PN
影响因子：
12.3
作者：
Brown MV;McDunn JE;Gunst PR;Smith EM;Milburn MV;Troyer DA;Lawton KA
通讯作者：
Lawton KA
影响因子：
29
作者：
Newgard CB
通讯作者：
Newgard CB
影响因子：
3.7
作者：
Gorden DL;Ivanova PT;Myers DS;McIntyre JO;VanSaun MN;Wright JK;Matrisian LM;Brown HA
通讯作者：
Brown HA
影响因子：
4.4
作者：
Kim, Hyun-Jin;Kim, Jin Hee;Yoon, Suk Hoo
通讯作者：
Yoon, Suk Hoo