Touchstone Diabetes Center.
Department of Molecular Genetics, and.
JCI Insight. 2019 Jul 16;5(15):129397. doi: 10.1172/jci.insight.129397.
The synthesis of lipid and sterol species through de novo lipogenesis (DNL) is regulated by two functionally overlapping but distinct transcription factors: the sterol regulatory element-binding proteins (SREBPs) and carbohydrate response element binding protein (ChREBP). ChREBP is considered to be the dominant regulator of DNL in adipose tissue (AT); however, the SREBPs are highly expressed and robustly regulated in adipocytes, suggesting that the model of AT DNL may be incomplete. Here we describe a new mouse model of inducible, adipocyte-specific overexpression of the insulin-induced gene 1 (Insig1), a negative regulator of SREBP transcriptional activity. Contrary to convention, Insig1 overexpression did block AT lipogenic gene expression. However, this was immediately met with a compensatory mechanism triggered by redox activation of mTORC1 to restore SREBP1 DNL gene expression. Thus, we demonstrate that SREBP1 activity sustains adipocyte lipogenesis, a conclusion that has been elusive due to the constitutive nature of current mouse models.
通过从头合成脂质和固醇（de novo lipogenesis，DNL）来合成脂质和固醇，受到两种功能上重叠但不同的转录因子的调节：固醇调节元件结合蛋白（sterol regulatory element-binding proteins，SREBPs）和碳水化合物反应元件结合蛋白（carbohydrate response element binding protein，ChREBP）。ChREBP 被认为是脂肪组织（adipose tissue，AT）中 DNL 的主要调节因子；然而，SREBPs 在脂肪细胞中高度表达且受到严格调控，这表明 AT DNL 的模型可能不完整。在这里，我们描述了一种新的诱导型、脂肪细胞特异性过表达胰岛素诱导基因 1（insulin-induced gene 1，Insig1）的小鼠模型，Insig1 是 SREBP 转录活性的负调节因子。与传统观点相反，Insig1 的过表达确实阻断了 AT 脂肪生成基因的表达。然而，这立即引发了一种由 mTORC1 的氧化还原激活触发的代偿机制，以恢复 SREBP1 的 DNL 基因表达。因此，我们证明了 SREBP1 的活性维持脂肪细胞的脂肪生成，由于目前的小鼠模型具有组成型特征，因此这个结论一直难以确定。
