The Actions of Orphan Nuclear Receptor RORgamma on Hepatic Cholesterol Metabolism in Piglets

概要

Time-restricted feeding (TRF) is a dieting strategy based on nutrients availability and diurnal rhythm, shown to improve lipid metabolism effi ciency. Previous study reveals that retinoic acid-related (RAR) orphan receptor (ROR) γ is closely linked to animal lipid metabolism. However, the functional role of RORγ in liver physiology of pigs in response to TRF has not been determined, largely due to the lack of functional models and molecular tools. We established porcine liver organoids and subjected them to restricted nutrients supply for 10-h during the light portion of the day. Our results showed that TRF regimen did not alter hepatocyte physiology but downregulated the hepatic CHO biosynthesis program along with the reduced cellular CHO content in porcine liver organoids. Using unbiased bioinformatic analysis of a previous ChIP-seq data and ChIP-qPCR validation, we revealed RORγ as the predominant transcription factor that responded to TRF. This was likely through RORγ direct binding to the MVK gene (encoding mevalonate kinase) and recruiting the enrichment of co-factor p300, histone marks H3K27ac and H3K4me1/2, as well as RNA Polymerase II (Pol-II) at the locus of MVK. Our fi ndings demonstrate that TRF triggers the RORγ-mediated chromatin remodeling at the locus of CHO biosynthesis genes in porcine liver organoids and further improves lipid metabolism.

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