Bile Acid Signal-induced Phosphorylation of Small Heterodimer Partner by Protein Kinase Cζ Is Critical for Epigenomic Regulation of Liver Metabolic Genes

• Published in: The Journal of biological chemistry 2013-08, Vol.288 (32), p.23252-23263
• Main Authors: Seok, Sunmi, Kanamaluru, Deepthi, Xiao, Zhen, Ryerson, Daniel, Choi, Sung-E, Suino-Powell, Kelly, Xu, H. Eric, Veenstra, Timothy D., Kemper, Jongsook Kim
• Format: Article
• Language: English
• Subjects: Animals; Bile Acid; Bile Acids and Salts - genetics; Bile Acids and Salts - metabolism; CDCA; Cyp7a1; Epigenesis, Genetic - physiology; Epigenomics; FGF19; Fibroblast Growth Factor (FGF); Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Hep G2 Cells; Histone Modification; Humans; Liver - metabolism; Male; Metabolism; Methylation; Mice; Mice, Inbred BALB C; Mutation; Phosphorylation - physiology; Post-translational Modification; Protein Kinase C-epsilon - genetics; Protein Kinase C-epsilon - metabolism; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Signal Transduction - physiology
• ISSN: 0021-9258; 1083-351X; 1083-351X
• DOI: 10.1074/jbc.M113.452037

Bile acids (BAs) are recently recognized key signaling molecules that control integrative metabolism and energy expenditure. BAs activate multiple signaling pathways, including those of nuclear receptors, primarily farnesoid X receptor (FXR), membrane BA receptors, and FXR-induced FGF19 to regulate the fed-state metabolism. Small heterodimer partner (SHP) has been implicated as a key mediator of these BA signaling pathways by recruitment of chromatin modifying proteins, but the key question of how SHP transduces BA signaling into repressive histone modifications at liver metabolic genes remains unknown. Here we show that protein kinase Cζ (PKCζ) is activated by BA or FGF19 and phosphorylates SHP at Thr-55 and that Thr-55 phosphorylation is critical for the epigenomic coordinator functions of SHP. PKCζ is coimmunopreciptitated with SHP and both are recruited to SHP target genes after bile acid or FGF19 treatment. Activated phosphorylated PKCζ and phosphorylated SHP are predominantly located in the nucleus after FGF19 treatment. Phosphorylation at Thr-55 is required for subsequent methylation at Arg-57, a naturally occurring mutation site in metabolic syndrome patients. Thr-55 phosphorylation increases interaction of SHP with chromatin modifiers and their occupancy at selective BA-responsive genes. This molecular cascade leads to repressive modifications of histones at metabolic target genes, and consequently, decreased BA pools and hepatic triglyceride levels. Remarkably, mutation of Thr-55 attenuates these SHP-mediated epigenomic and metabolic effects. This study identifies PKCζ as a novel key upstream regulator of BA-regulated SHP function, revealing the role of Thr-55 phosphorylation in epigenomic regulation of liver metabolism. Background: Small heterodimer partner (SHP) is a key mediator of bile acid signaling. Results: Bile acid signal-induced phosphorylation at Thr-55 by protein kinase Cζ is important for SHP-mediated recruitment of chromatin modifiers and histone modifications. Conclusion: Thr-55 phosphorylation is critical for epigenomic regulation of liver metabolic genes. Significance: SHP Thr-55 phosphorylation may potentially provide a therapeutic target for bile acid-related diseases.