Department of Microbiology and Molecular Genetics, College of Biological Sciences, University of California at Davis, Davis, California, United States of America.
Department of Molecular Biosciences, School of Veterinary Medicine and Mouse Metabolic Phenotyping Center, Microbiome & Host Response Core, University of California at Davis, Davis, California, United States of America.
PLoS One. 2020 Oct 26;15(10):e0241238. doi: 10.1371/journal.pone.0241238. eCollection 2020.
The NCoR corepressor plays critical roles in mediating transcriptional repression by both nuclear receptors and non-receptor transcription factors. Alternative mRNA splicing of NCoR produces a series of variants with differing molecular and biological properties. The NCoRω splice-variant inhibits adipogenesis whereas the NCoRδ splice-variant promotes it, and mice bearing a splice-specific knockout of NCoRω display enhanced hepatic steatosis and overall weight gain on a high fat diet as well as a greatly increased resistance to diet-induced glucose intolerance. We report here that the reciprocal NCoRδ splice-specific knock-out mice display the contrary phenotypes of reduced hepatic steatosis and reduced weight gain relative to the NCoRω-/- mice. The NCoRδ-/- mice also fail to demonstrate the strong resistance to diet-induced glucose intolerance exhibited by the NCoRω-/- animals. The NCoR δ and ω variants possess both unique and shared transcriptional targets, with expression of certain hepatic genes affected in opposite directions in the two mutants, others altered in one but not the other genotype, and yet others changed in parallel in both NCoRδ-/- and NCoRω-/- animals versus WT. Gene set expression analysis (GSEA) identified a series of lipid, carbohydrate, and amino acid metabolic pathways that are likely to contribute to their distinct steatosis and glucose tolerance phenotypes. We conclude that alternative-splicing of the NCoR corepressor plays a key role in the regulation of hepatic energy storage and utilization, with the NCoRδ and NCoRω variants exerting both opposing and shared functions in many aspects of this phenomenon and in the organism as a whole.
NCoR 核心抑制因子在介导核受体和非受体转录因子的转录抑制中发挥关键作用。NCoR 的选择性剪接产生了一系列具有不同分子和生物学特性的变体。NCoRω 剪接变体抑制脂肪生成，而 NCoRδ 剪接变体促进脂肪生成，并且携带 NCoRω 剪接特异性敲除的小鼠在高脂肪饮食下表现出增强的肝脂肪变性和总体体重增加，以及对饮食诱导的葡萄糖不耐受的极大增强抗性。我们在这里报告，相反的 NCoRδ 剪接特异性敲除小鼠表现出相对于 NCoRω-/-小鼠减少的肝脂肪变性和减少的体重增加的表型。NCoRδ-/-小鼠也未能表现出 NCoRω-/-动物所表现出的对饮食诱导的葡萄糖不耐受的强烈抗性。NCoRδ 和 ω 变体都具有独特和共享的转录靶标，某些肝基因的表达在两种突变体中以相反的方向受到影响，其他基因在一种基因型中改变而在另一种基因型中不改变，而其他基因在 NCoRδ-/-和 NCoRω-/-动物中与 WT 相比以平行方式改变。基因集表达分析（GSEA）鉴定了一系列可能有助于其不同的脂肪变性和葡萄糖耐量表型的脂质、碳水化合物和氨基酸代谢途径。我们得出结论，NCoR 核心抑制因子的选择性剪接在肝脏能量储存和利用的调节中发挥关键作用，NCoRδ 和 NCoRω 变体在这一现象的许多方面以及整个生物体中发挥着相反和共同的作用。
