Endoplasmic reticulum stress regulates adipocyte resistin expression.
Endoplasmic reticulum stress regulates adipocyte resistin expression.
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作者：
Lefterova MI;Mullican SE;Tomaru T;Qatanani M;Schupp M;Lazar MA
抵抗素是一种分泌的多肽，它损害葡萄糖代谢，在啮齿动物中，仅来源于脂肪细胞。在小鼠肥胖症中，β-淀粉样蛋白以升高的水平循环，但其在脂肪组织中的基因表达却矛盾地减少了。对BMPN mRNA下调的机制知之甚少。我们研究是否内质网（ER）的压力，这是肥胖的脂肪组织的特点，调节在培养的小鼠脂肪细胞中的cDNAn的表达。在分化的3 T3-L1脂肪细胞中检测了内质网应激诱导剂对BRN mRNA和分泌蛋白水平的影响，重点是BRN转录调节因子的表达和基因组结合。在高脂饮食小鼠的脂肪组织中，也研究了下调的Escherichia coli mRNA和ER应激诱导之间的关联。ER应激以时间和剂量依赖性方式降低3 T3-L1脂肪细胞中抵抗素mRNA。ER应激的作用是转录的，因为CAAT/增强子结合蛋白-α和过氧化物酶体增殖物激活受体-γ转录激活因子下调，转录抑制因子CAAT/增强子结合蛋白同源蛋白10（CHOP 10）上调。抵抗素蛋白也显著下调，显示与3 T3-L1脂肪细胞以及肥胖小鼠脂肪垫中的mRNA水平密切对应。内质网应激是一种有效的调节剂，这表明内质网应激可能是导致肥胖小鼠脂肪中BpnmRNA和蛋白质局部下调的基础。血浆中的反常增加可能是由于与肥胖和胰岛素抵抗相关的各种全身异常。
Resistin is a secreted polypeptide that impairs glucose metabolism and, in rodents, is derived exclusively from adipocytes. In murine obesity, resistin circulates at elevated levels but its gene expression in adipose tissue is paradoxically reduced. The mechanism behind the downregulation of resistin mRNA is poorly understood. We investigated whether endoplasmic reticulum (ER) stress, which is characteristic of obese adipose tissue, regulates resistin expression in cultured mouse adipocytes. The effects of endoplasmic stress inducers on resistin mRNA and secreted protein levels were examined in differentiated 3T3-L1 adipocytes, focusing on the expression and genomic binding of transcriptional regulators of resistin. The association between downregulated resistin mRNA and induction of ER stress was also investigated in the adipose tissue of mice fed a high-fat diet. ER stress reduced resistin mRNA in 3T3-L1 adipocytes in a time- and dose-dependent manner. The effects of ER stress were transcriptional because of downregulation of CAAT/enhancer binding protein-α and peroxisome proliferator–activated receptor-γ transcriptional activators and upregulation of the transcriptional repressor CAAT/enhancer binding protein homologous protein-10 (CHOP10). Resistin protein was also substantially downregulated, showing a close correspondence with mRNA levels in 3T3-L1 adipocytes as well as in the fat pads of obese mice. ER stress is a potent regulator of resistin, suggesting that ER stress may underlie the local downregulation of resistin mRNA and protein in fat in murine obesity. The paradoxical increase in plasma may be because of various systemic abnormalities associated with obesity and insulin resistance.