Alpha-syntrophin null mice are protected from non-alcoholic steatohepatitis in the methionine-choline-deficient diet model but not the atherogenic diet model.
Alpha-syntrophin null mice are protected from non-alcoholic steatohepatitis in the methionine-choline-deficient diet model but not the atherogenic diet model.
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DOI：
10.1016/j.bbalip.2018.02.006
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发表时间：
2018-05
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通讯作者：
L. Rein‐Fischboeck;E. Haberl;R. Pohl;V. Schmid;S. Feder;S. Krautbauer;G. Liebisch;C. Buechler
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文献类型：
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作者：
L. Rein‐Fischboeck;E. Haberl;R. Pohl;V. Schmid;S. Feder;S. Krautbauer;G. Liebisch;C. Buechler
脂肪组织功能障碍有助于非酒精性脂肪性肝炎（NASH）的发病机制。衔接蛋白α-突触营养蛋白（SNTA）在脂肪细胞中表达。SNTA的敲低增加前脂肪细胞增殖和小脂滴的形成，这两者都是健康脂肪组织的特征。为了阐明SNTA在NASH中的潜在保护作用，对SNTA缺失小鼠喂食蛋氨酸胆碱缺乏（MCD）饲料或致动脉粥样硬化饲料，这些饲料被广泛用作临床前NASH模型。与相应的野生型动物相比，SNTA−/−小鼠中MCD饲料介导的脂肪量损失大幅改善。肝脏脂质大部分不变，而氧化应激标志物丙二醛仅在野生型小鼠中诱导。在SNTA−/−动物中，炎症标志物的表达和巨噬细胞向肝脏的迁移减少。这种SNTA损失的保护功能在致动脉粥样硬化饮食诱导的NASH中不存在。在这里，肝脏表达的炎症和纤维化基因在两种基因型是相似的，虽然突变小鼠获得较少的体脂肪在喂养过程中。在喂食致动脉粥样硬化饮食后，两种品系中的肝脏胆固醇和神经酰胺被强烈诱导，而肝脏鞘磷脂、磷脂酰丝氨酸和磷脂酰乙醇胺水平被抑制。由致动脉粥样硬化饮食诱导的NASH不受SNTA损失的影响。本研究建议使用不同的实验NASH模型来研究蛋白质如SNTA在NASH中的病理生理作用。
Adipose tissue dysfunction contributes to the pathogenesis of non-alcoholic steatohepatitis (NASH). The adapter protein alpha-syntrophin (SNTA) is expressed in adipocytes. Knock-down of SNTA increases preadipocyte proliferation and formation of small lipid droplets, which are both characteristics of healthy adipose tissue. To elucidate a potential protective role of SNTA in NASH, SNTA null mice were fed a methionine-choline-deficient (MCD) diet or an atherogenic diet which are widely used as preclinical NASH models. MCD diet mediated loss of fat mass was largely improved in SNTA−/− mice compared to the respective wild type animals. Hepatic lipids were mostly unchanged while the oxidative stress marker malondialdehyde was only induced in the wild type mice. The expression of inflammatory markers and macrophage immigration into the liver were reduced in SNTA−/− animals. This protective function of SNTA loss was absent in atherogenic diet induced NASH. Here, hepatic expression of inflammatory and fibrotic genes was similar in both genotypes though mutant mice gained less body fat during feeding. Hepatic cholesterol and ceramide were strongly induced in both strains upon feeding the atherogenic diet, while hepatic sphingomyelin, phosphatidylserine and phosphatidylethanolamine levels were suppressed.SNTA deficient mice are protected from fat loss and NASH in the experimental MCD model. NASH induced by an atherogenic diet is not influenced by loss of SNTA. The present study suggests the use of different experimental NASH models to study the pathophysiological role of proteins like SNTA in NASH.