An HDAC3-PROX1 corepressor module acts on HNF4 alpha to control hepatic triglycerides

作者：Armour Sean M; Rem**erg Jarrett R; Damle Manashree; Sidoli Simone; Ho Wesley Y; Li Zhenghui; Garcia Benjamin A; Lazar Mitchell A

来源：Nature Communications, 2017, 8(1): 54.

DOI：10.1038/s41467-017-00772-5

The histone deacetylase HDAC3 is a critical mediator of hepatic lipid metabolism, and liver-specific deletion of HDAC3 leads to fatty liver. To elucidate the underlying mechanism, here we report a method of cross-linking followed by mass spectrometry to define a high-confidence HDAC3 interactome in vivo that includes the canonical NCoR-HDAC3 complex as well as Prospero-related homeobox 1 protein (PROX1). HDAC3 and PROX1 co-localize extensively on the mouse liver genome, and are co-recruited by hepatocyte nuclear factor 4 alpha (HNF4 alpha). The HDAC3-PROX1 module controls the expression of a gene program regulating lipid homeostasis, and hepatic-specific ablation of either component increases triglyceride content in liver. These findings underscore the importance of specific combinations of transcription factors and coregulators in the fine tuning of organismal metabolism.

• 出版日期2017-9-15