Molecular analysis of the mouse brain exposed to chronic mild stress: The influence of hepatocyte nuclear factor 4α on physiological homeostasis
Molecular analysis of the mouse brain exposed to chronic mild stress: The influence of hepatocyte nuclear factor 4α on physiological homeostasis
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DOI：
10.3892/mmr.2017.6577
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发表时间：
2017-07-01
影响因子：
3.4
通讯作者：
Matsunaga, Hisato
中科院分区：
文献类型：
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作者：
Ikubo, Kaoru;Yamanishi, Kyosuke;Matsunaga, Hisato
重性抑郁障碍（MDD）是一种流行的疾病，导致相当大的残疾，在社会功能，是一个危险因素，身体疾病。最近的临床报告表明，MDD与代谢紊乱（包括糖尿病、激素异常和自身免疫性疾病）引起的生理性稳态障碍之间存在显著相关性。本研究的作者先前分析了慢性轻度应激（CMS）MDD动物模型的前额叶皮层（PFC）的比较基因表达谱。肝细胞核因子4 α（Hnf 4 α）被认为是一种对生理稳态相关基因产生重要影响的中枢调节因子。本研究的目的是调查：i）PFC中抑郁状态的分子机制，以及ii）从比较基因表达谱中提取的基因的参与，特别是那些适用于临床实践中的MDD。使用不相容性途径分析（IPA）对先前PFC微阵列结果进行核心分析。随后，使用IPA来搜索由Hnf 4 α调节并存在于PFC和血清中的分子。从核心分析中，选择了5个与细胞死亡相关并在皮质中表达的基因。四个提取的基因，胰岛素样生长因子1，甲状腺素运载蛋白，丝氨酸蛋白酶抑制剂家族A成员3和纤溶酶原，显着影响HNF 4 α。还选择了S100钙结合蛋白A9（S100 a9）和α 2-HS-糖蛋白（Ahsg），因为它们存在于血清中，也受Hnf 4 α的影响。在PFC、丘脑和海马中检测到这两个基因的表达存在显著的组间差异。与对照组相比，CMS组PFC和海马中AHSG和S100 A9蛋白水平显著升高。这些发现支持Hnf 4 α（通过S100 a9和Ahsg等基因）与MDD进展期间生理稳态失调诱导的各种疾病的发展密切相关。
Major depressive disorder (MDD) is a prevalent disorder that causes considerable disability in social functioning and is a risk factor for physical diseases. Recent clinical reports have demonstrated a marked association between MDD and physiological dyshomeostasis induced by metabolic disorders, including diabetes, hormone abnormalities and autoimmune diseases. The authors of the present study have previously analyzed comparative gene expression profiles in the prefrontal cortex (PFC) of a chronic mild stress (CMS) animal model of MDD. Hepatocyte nuclear factor 4 alpha (Hnf4 alpha) was identified as a central regulator that exerted significant influence on genes associated with physiological homeostasis. The aim of the present study was to investigate: i) the molecular mechanism of the depressive state in the PFC, and ii) the involvement of genes extracted from the comparative gene expression profiles, particularly those applicable to MDD in clinical practice. Core analysis of the previous PFC microarray results was performed using Ingenuity Pathway Analysis (IPA). Subsequently, IPA was used to search for molecules that are regulated by Hnf4 alpha, and exist in the PFC and serum. From the core analysis, 5 genes that are associated with cell death and are expressed in the cortex were selected. Four of the extracted genes, insulin-like growth factor 1, transthyretin, serpin family A member 3 and plasminogen, were markedly affected by Hnf4 alpha. S100 calcium-binding protein A9 (S100a9) and alpha 2-HS-glycoprotein (Ahsg) were also chosen as they exist in serum and are also affected by Hnf4 alpha. A significant group difference in the expression of these two genes was detected in the PFC, thalamus and hippocampus. The protein levels of AHSG and S100A9 in the PFC and hippocampus of the CMS group increased significantly when compared with the control group. These findings support the close association of Hnf4 alpha (through genes such as S100a9 and Ahsg) with the development of various diseases induced by deregulation of physiological homeostasis during the progression of MDD.