Aryl-hydrocarbon receptor is an inhibitory regulator of lipid synthesis and of commitment to adipogenesis.
Aryl-hydrocarbon receptor is an inhibitory regulator of lipid synthesis and of commitment to adipogenesis.
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发表时间：
1998-11
影响因子：
4
通讯作者：
D. L. Alexander;L. G. Ganem;P. Fernández-Salguero;F. Gonzalez;C. Jefcoate
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作者：
D. L. Alexander;L. G. Ganem;P. Fernández-Salguero;F. Gonzalez;C. Jefcoate
芳烃受体（AhR）是一种介导2,3,7,8 -四氯二苯并-对二恶英（TCDD）生物效应的配体依赖性转录因子。在小鼠胚胎成纤维细胞中，TCDD激活多种基因的表达，包括在这些细胞中表达的主要细胞色素P450 CYP1B1。在这里，我们分析了原代小鼠胚胎成纤维细胞（MEF）和来自野生型（WT） C57BL/6小鼠以及AhR基因靶向破坏（AhR-/-）的同源小鼠的自发永生化MEF细胞系中AhR的组成功能。经过多次传代，原代mef表现为自发分化、生长停止和衰老。最终，永生化mef的菌落形成无性系。对于AhR-/- mef，衰老阶段发生得更早，而永生化则大大延迟。AhR-/-和WT mef的比较也表明，组成性AhR活性是CYP1B1基础表达和抑制亚融合培养中脂肪生成所必需的。原生WT和AhR-/- mef以及相应的细胞系在与适当的激素诱导剂汇合时发生脂肪生成。通过脂质积累、甘油磷酸脱氢酶活性和硬脂酰辅酶a去饱和酶1型mRNA表达来测定，在激素诱导之前或同时添加TCDD可抑制PPAR γ mRNA和脂肪形成。在AhR-/- mef中，TCDD治疗的这种效果不存在，这证实了AhR在激素诱导的脂肪形成中的作用。这种融合mef和前脂肪细胞的激素激活导致有限的增殖扩张，随后是不可逆的生长停滞。经tcdd处理的mef进行有丝分裂扩增，但不能退出细胞周期。在AhR-/- mef中，TCDD没有这种作用。这些发现暗示AhR作为甘油三酯合成的组成抑制剂，并作为脂肪细胞分化的早期调节剂。AhR干扰细胞周期阻滞的分化可能与衰老率的增加有关。
The aryl-hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that mediates the biological effects of 2,3,7, 8-tetrachlorodibenzo-p-dioxin (TCDD). In mouse embryo fibroblasts, TCDD activates expression of multiple genes, including CYP1B1, the predominant cytochrome P450 expressed in these cells. Here, we analyze constitutive functions of the AhR in primary mouse embryo fibroblasts (MEFs) and spontaneously immortalized MEF cell lines derived from wild-type (WT) C57BL/6 mice and also from congenic mice with a targeted disruption of the AhR gene (AhR-/-). After multiple passages, primary MEFs exhibit spontaneous differentiation, growth cessation and senescence. Eventually, colonies of immortalized MEFs arise to provide clonal lines. The senescent phase occurs much earlier for AhR-/- MEFs, while immortalization is substantially delayed. Comparison of AhR-/- and WT MEFs also indicates that constitutive AhR activity is required for basal expression of CYP1B1 and suppresses lipogenesis in subconfluent cultures. Primary WT and AhR-/- MEFs and the corresponding lines undergo adipogenesis when treated at confluence with the appropriate hormonal inducers. Addition of TCDD before or concurrent with hormonal induction suppressed PPAR gamma mRNA and adipogenesis, as measured by lipid accumulation, glycerol phosphate dehydrogenase activity and stearoyl CoA desaturase type 1 mRNA expression. This effect of TCDD treatment was absent in AhR-/- MEFs, establishing the role of AhR in hormone-induced adipogenesis. Such hormonal activation of confluent MEFs and preadipocytes results in a limited proliferative expansion followed by irreversible growth arrest. TCDD-treated MEFs undergo the mitotic expansion but fail to exit the cell cycle. In AhR-/- MEFs, there is no such effect of TCDD. These findings implicate the AhR as a constitutive inhibitor of triglyceride synthesis, and as an early regulator of adipocyte differentiation. AhR interference with cell-cycle arrest in differentiation may be linked to the increased rate of senescence.