Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers.
Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers.
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DOI：
10.1038/s41366-018-0062-9
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Katagiri H
中科院分区：
文献类型：
--
作者：
Honma M;Sawada S;Ueno Y;Murakami K;Yamada T;Gao J;Kodama S;Izumi T;Takahashi K;Tsukita S;Uno K;Imai J;Kakazu E;Kondo Y;Mizuno K;Kawagishi N;Shimosegawa T;Katagiri H
胰岛素信号通过调节关键酶的表达，抑制肝脏中的脂质生成并增强脂质合成。动物研究表明，在脂肪变性肝脏中，胰岛素信号转导有利于抑制肝脏再生，从而选择性受损。然而，这种选择性胰岛素抵抗是否以及如何发生在人类脂肪肝中仍然未知。我们的目的是研究非酒精性脂肪性肝病（NAFLD）患者肝脏的选择性胰岛素抵抗。我们检测了来自51名非糖尿病受试者（9名健康对照和42名NAFLD患者）的人类肝活检样本中胰岛素信号传导、脂肪生成和脂肪生成关键分子的mRNA表达，并分析了这些分子彼此之间的关联以及详细的病理学和临床生化数据。在NAFLD患者中，胰岛素受体底物（IRS）-2的表达降低，而这些关键酶的表达增加。在单纯性脂肪变性（SS）和非酒精性脂肪性肝炎（NASH）中均诱导IRS-2和肝脏生成酶的这些改变，而这些表达水平在SS和NASH之间没有差异。此外，IRS-2和血管生成酶的表达变化表现出强烈的负相关性，并在NAFLD的早期组织学阶段同时诱导。与此相反，脂肪酸合成酶（FAS）的表达没有减少NAFLD，尽管IRS-2下调，但与IRS-1的表达密切相关。此外，组织学评分与这些分子无关。因此，IRS-1信号，这是不受NAFLD，似乎调节FAS的表达。这些分析表明，选择性胰岛素抵抗存在于人类NAFLD肝脏中，并发生在其早期阶段。在IRS步骤中，胰岛素对脂肪生成和脂肪生成的基因表达的影响是明显不同的，IRS-2的优先下调可能有助于对胰岛素对脂肪生成的抑制作用的选择性抗性。
Insulin signals, via the regulation of key enzyme expression, both suppress gluconeogenesis and enhance lipid synthesis in the liver. Animal studies have revealed insulin signaling favoring gluconeogenesis suppression to be selectively impaired in steatotic livers. However, whether, and if so how, such selective insulin resistance occurs in human steatotic livers remains unknown. Our aim was to investigate selective insulin resistance in human livers with non-alcoholic fatty liver disease (NAFLD). We examined mRNA expressions of key molecules for insulin signaling, gluconeogenesis and lipogenesis in human liver biopsy samples obtained from 51 non-diabetic subjects: 9 healthy controls and 42 NAFLD patients, and analyzed associations of these molecules with each other and with detailed pathological and clinical biochemistry data. In NAFLD patients, insulin receptor substrate (IRS)-2 expression was decreased, while those of key enzymes for gluconeogenesis were increased. These alterations of IRS-2 and gluconeogenesis enzymes were induced both in simple steatosis (SS) and non-alcoholic steatohepatitis (NASH), while these expression levels did not differ between SS and NASH. Furthermore, alterations in the expressions of IRS-2 and gluconeogenesis enzymes showed strong negative correlations and were concurrently induced in the early histological stage of NAFLD. In contrast, fatty acid synthase (FAS) expression was not decreased in NAFLD, despite IRS-2 downregulation, but correlated strongly with IRS-1 expression. Furthermore, no histological scores were associated with these molecules. Thus, IRS-1 signaling, which is not impaired in NAFLD, appears to modulate FAS expression. These analyses revealed that selective insulin resistance is present in human NAFLD livers and occurs in its early phases. The effect of insulin, during the IRS step, on gene expressions for lipogenesis and gluconeogenesis are apparently distinct and preferential downregulation of IRS-2 may contribute to selective resistance to the suppressive effects of insulin on gluconeogenesis.
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