通过 PRDM16-GTF2IRD1 复合物抑制脂肪组织纤维化可改善全身葡萄糖稳态。
Repression of Adipose Tissue Fibrosis through a PRDM16-GTF2IRD1 Complex Improves Systemic Glucose Homeostasis.
机构信息
UCSF Diabetes Center, San Francisco, CA, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA; Division of Diabetes and Metabolism, Department of Internal Medicine, Iwate Medical University, Morioka, Uchimaru, Japan.
UCSF Diabetes Center, San Francisco, CA, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, San Francisco, CA, USA; Department of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.
出版信息
Cell Metab. 2018 Jan 9;27(1):180-194.e6. doi: 10.1016/j.cmet.2017.12.005.
Adipose tissue fibrosis is a hallmark of malfunction that is linked to insulin resistance and type 2 diabetes; however, what regulates this process remains unclear. Here we show that the PRDM16 transcriptional complex, a dominant activator of brown/beige adipocyte development, potently represses adipose tissue fibrosis in an uncoupling protein 1 (UCP1)-independent manner. By purifying the PRDM16 complex, we identified GTF2IRD1, a member of the TFII-I family of DNA-binding proteins, as a cold-inducible transcription factor that mediates the repressive action of the PRDM16 complex on fibrosis. Adipocyte-selective expression of GTF2IRD1 represses adipose tissue fibrosis and improves systemic glucose homeostasis independent of body-weight loss, while deleting GTF2IRD1 promotes fibrosis in a cell-autonomous manner. GTF2IRD1 represses the transcription of transforming growth factor β-dependent pro-fibrosis genes by recruiting PRDM16 and EHMT1 onto their promoter/enhancer regions. These results suggest a mechanism by which repression of obesity-associated adipose tissue fibrosis through the PRDM16 complex leads to an improvement in systemic glucose homeostasis.
脂肪组织纤维化是功能障碍的一个标志，与胰岛素抵抗和 2 型糖尿病有关；然而，调节这一过程的机制尚不清楚。在这里，我们表明 PRDM16 转录复合物是棕色/米色脂肪细胞发育的主要激活剂，能够以独立于解偶联蛋白 1 (UCP1)的方式强烈抑制脂肪组织纤维化。通过纯化 PRDM16 复合物，我们鉴定出 GTF2IRD1，一种 DNA 结合蛋白 TFII-I 家族的成员，作为介导 PRDM16 复合物对纤维化的抑制作用的冷诱导转录因子。脂肪细胞选择性表达 GTF2IRD1 可抑制脂肪组织纤维化并改善全身葡萄糖稳态，而不依赖于体重减轻，而删除 GTF2IRD1 则以细胞自主的方式促进纤维化。GTF2IRD1 通过将 PRDM16 和 EHMT1 募集到其启动子/增强子区域，抑制转化生长因子 β 依赖性促纤维化基因的转录。这些结果表明，通过 PRDM16 复合物抑制肥胖相关的脂肪组织纤维化可改善全身葡萄糖稳态的机制。
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