Specific ablation of the NCoR corepressor δ splice variant reveals alternative RNA splicing as a key regulator of hepatic metabolism

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 NCoR omega splice-variant inhibits adipogenesis whereas the NCoR delta splice-variant promotes it, and mice bearing a splice-specific knockout of NCoR omega 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 NCoR delta splice-specific knock-out mice display the contrary phenotypes of reduced hepatic steatosis and reduced weight gain relative to the NCoR omega-/- mice. The NCoR delta-/- mice also fail to demonstrate the strong resistance to diet-induced glucose intolerance exhibited by the NCoR omega-/- animals. The NCoR delta and omega 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 NCoR delta-/- and NCoR omega-/- 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 NCoR delta and NCoR omega variants exerting both opposing and shared functions in many aspects of this phenomenon and in the organism as a whole.