ABSTRACT
Carbohydrate response element binding protein (ChREBP) is a key transcriptional regulator of de novo lipogenesis (DNL) in response to carbohydrates and in hepatic steatosis. Mechanisms underlying nutrient modulation of ChREBP are under active investigation. Here we identify host cell factor 1 (HCF-1) as a previously unknown ChREBP-interacting protein that is enriched in liver biopsies of nonalcoholic steatohepatitis (NASH) patients. Biochemical and genetic studies show that HCF-1 is O-GlcNAcylated in response to glucose as a prerequisite for its binding to ChREBP and subsequent recruitment of OGT, ChREBP O-GlcNAcylation, and activation. The HCF-1:ChREBP complex resides at lipogenic gene promoters, where HCF-1 regulates H3K4 trimethylation to prime recruitment of the Jumonji C domain-containing histone demethylase PHF2 for epigenetic activation of these promoters. Overall, these findings define HCF-1's interaction with ChREBP as a previously unappreciated mechanism whereby glucose signals are both relayed to ChREBP and transmitted for epigenetic regulation of lipogenic genes.
Subject(s)
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics , Homeodomain Proteins/genetics , Host Cell Factor C1/genetics , Lipogenesis/genetics , Non-alcoholic Fatty Liver Disease/genetics , Animals , Carbohydrates/genetics , Epigenesis, Genetic , Gene Expression Regulation , Glucose/metabolism , Hexosamines/genetics , Hexosamines/metabolism , Humans , Liver/metabolism , Mice , Non-alcoholic Fatty Liver Disease/pathology , Promoter Regions, Genetic/genetics , Protein Interaction Maps/geneticsABSTRACT
Metabolic alteration, either through the ketogenic diet (KD) or by genetic alteration of the BAD protein, can produce seizure protection in acute chemoconvulsant models of epilepsy. To assess the seizure-protective role of knocking out (KO) the Bad gene in a chronic epilepsy model, we used the Kcna1-/- model of epilepsy, which displays progressively increased seizure severity and recapitulates the early death seen in sudden unexplained death in epilepsy (SUDEP). Beginning on postnatal day 24 (P24), we continuously video monitored Kcna1-/- and Kcna1-/- Bad-/- double knockout mice to assess survival and seizure severity. We found that Kcna1-/- Bad-/- mice outlived Kcna1-/- mice by approximately 2 weeks. Kcna1-/- Bad-/- mice also spent significantly less time in seizure than Kcna1-/- mice on P24 and the day of death, showing that BadKO provides seizure resistance in a genetic model of chronic epilepsy.
