Altered hepatic lipid metabolism in mice lacking both the melanocortin type 4 receptor and low density lipoprotein receptor.
Altered hepatic lipid metabolism in mice lacking both the melanocortin type 4 receptor and low density lipoprotein receptor.
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DOI：
10.1371/journal.pone.0172000
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Schiller J
中科院分区：
文献类型：
--
作者：
Lede V;Meusel A;Garten A;Popkova Y;Penke M;Franke C;Ricken A;Schulz A;Kiess W;Huster D;Schöneberg T;Schiller J
肥胖通常与血脂异常和脂肪肝有关。建立了许多非酒精性脂肪性肝病（NAFLD）的动物模型，但它们在分子和生化变化方面存在显着差异，这取决于所使用的遗传修饰和饮食。黑皮质素4型受体（Mc 4 rmut）缺陷的小鼠在常规食物下已经发展为摄食过多、肥胖和随后的NAFLD，并且更接近于在人类中发现的能量供应驱动的肥胖。该动物模型被用来评估高吞噬诱导的肥胖对肝脏脂质代谢的分子和生化后果。我们通过RNA测序分析了Mc 4 rmut小鼠的转录组变化，并使用高分辨率1H魔角旋转NMR光谱和MALDI-TOF质谱来评估脂质组成的变化。在转录组水平上，我们发现与野生型相比，三酰甘油代谢，不饱和脂肪酸生物合成，过氧化物酶体增殖物激活受体信号通路以及脂质转运和储存的组分发生了显着变化。三酰甘油、单不饱和脂肪酸和花生四烯酸水平的增加支持了这些发现。转录组特征与其他NAFLD小鼠模型的转录组特征显著不同，支持肝亚表型取决于遗传背景和饮食的概念。我们的数据与以前的研究进行比较分析，可以识别与肥胖相关的NAFLD的共同变化和基因型特异性成分和途径。
Obesity is often associated with dyslipidemia and hepatosteatosis. A number of animal models of non-alcoholic fatty liver disease (NAFLD) are established but they significantly differ in the molecular and biochemical changes depending on the genetic modification and diet used. Mice deficient for melanocortin type 4 receptor (Mc4rmut) develop hyperphagia, obesity, and subsequently NAFLD already under regular chow and resemble more closely the energy supply-driven obesity found in humans. This animal model was used to assess the molecular and biochemical consequences of hyperphagia-induced obesity on hepatic lipid metabolism. We analyzed transcriptome changes in Mc4rmut mice by RNA sequencing and used high resolution 1H magic angle spinning NMR spectroscopy and MALDI-TOF mass spectrometry to assess changes in the lipid composition. On the transcriptomic level we found significant changes in components of the triacylglycerol metabolism, unsaturated fatty acids biosynthesis, peroxisome proliferator-activated receptor signaling pathways, and lipid transport and storage compared to the wild-type. These findings were supported by increases in triacylglycerol, monounsaturated fatty acid, and arachidonic acid levels. The transcriptome signatures significantly differ from those of other NAFLD mouse models supporting the concept of hepatic subphenotypes depending on the genetic background and diet. Comparative analyses of our data with previous studies allowed for the identification of common changes and genotype-specific components and pathways involved in obesity-associated NAFLD.