FoxK1-Associated Gene Regulatory Network-A New Transcriptional Regulator of Hepatic Insulin Action

Insulin acts on the liver to maintain glucose homeostasis, and disruption of insulin action in liver is central in the pathogenesis of diabetes and metabolic syndrome. While most previous studies of insulin action on gene expression in liver have focused on FoxO1, we have found that Forkhead box protein K1 (FoxK1) is another important regulator of hepatic gene expression which acts in a complementary manner. Thus, upon insulin stimulation, FoxK1 translocates from the cytoplasm to nucleus while FoxO1 translocates from nucleus to cytoplasm. Chromatin immunoprecipitation (ChIP) sequencing shows that FoxK1 binds to >1000 gene regulatory elements in the proximal promoters and enhancers in hepatic chromatin, with TGTTTAC being the major FoxK1 DNA binding motif. De novo motif analysis suggested that HNF4A is also one of the major co-regulators for FoxK1 in mediating gene expression. Insulin stimulated binding of FoxK1 to promoters was observed in up-regulation of genes involved in steroid biosynthesis and cell cycle, and down-regulation of genes involved in autophagy. FoxK1 is also a potential transcription factor for insulin receptor (IRβ) mediated gene regulation as evidenced by its binding to LARS1 and TIMM22 promoters. Both FoxK1 and IRβ share regulation of genes involved in rRNA processing, mitotic cell cycle and nonsense-mediated decay. Interestingly, gene promoters of genes in glucose metabolism (PCK1, G6PC and PKM) are bound by FoxK1, but not by IRβ in response to insulin. FoxK1 can also work with FoxO1 in regulation of genes involved in mitochondrial translation, and with both IRβ and FoxO1 in insulin regulation of AHCY, PPRC1, and CDKN1A, i.e., genes involved in cell senescence, amino acid metabolism and mitochondrial biogenesis. Thus, FoxK1 is a potential factor priming the response to insulin and helps with the recruitment of IRβ or FoxO1 in regulation of gene expression in liver in metabolism and other important biological pathways. Disclosure P.Allu: None. H.Pan: None. J.Dreyfuss: None. C.Kahn: None.