Key result
Proline hydroxylation of ChREBP is required for its adequate activation upon exposure to high glucose and subsequent target gene expression in hepatocytes.
Proline hydroxylation is a novel post-translational modification required for ChREBP activation by high glucose, presenting a potential therapeutic target for metabolic diseases.
Cellular energy demands are met by uptake and metabolism of nutrients like glucose. The principal transcriptional regulator for adapting glycolytic flux and downstream pathways like de novo lipogenesis to glucose availability in many cell types is carbohydrate response element–binding protein (ChREBP). ChREBP is activated by glucose metabolites and post-translational modifications, inducing nuclear accumulation and regulation of target genes. Here we report that ChREBP is modified by proline hydroxylation at several residues. Proline hydroxylation targets both ectopically expressed ChREBP in cells and endogenous ChREBP in mouse liver. Functionally, we found that specific hydroxylated prolines were dispensable for protein stability but required for the adequate activation of ChREBP upon exposure to high glucose. Accordingly, ChREBP target gene expression was rescued by re-expressing WT but not ChREBP that lacks hydroxylated prolines in ChREBP-deleted hepatocytes. Thus, proline hydroxylation of ChREBP is a novel post-translational modification that may allow for therapeutic interference in metabolic diseases.
No takes yet. Share an insight, caveat, or question.
Heidenreich et al. (2020) studied this question. Proline hydroxylation of ChREBP was evaluated on ChREBP activation and target gene expression. Proline hydroxylation of ChREBP is required for its adequate activation upon exposure to high glucose and subsequent target gene expression in hepatocytes.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: