Pharmaceutical Sciences Faculty Publications
Document Type
Article
Publication Date
8-9-2013
Journal Title
Journal of Biological Chemistry
ISSN
1083-351X
Volume
288
Issue
32
First Page
23252
Last Page
23263
DOI
10.1074/jbc.M113.452037
PubMed ID
23824184
Abstract
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.
Keywords
Bile acids, salts, epigenesis, genetic, liver, signal transduction
Recommended Citation
Seok, Sunmi; Kanamaluru, Deepthi; Xiao, Zhen; Ryerson, Daniel; Choi, Sung-E; Suino-Powell, Kelly; Xu, H. Eric; Veenstra, Timothy D.; and Kemper, Jongsook Kim, "Bile Acid Signal-Induced Phosphorylation of Small Heterodimer Partner by Protein Kinase Cζ is Critical for Epigenomic Regulation of Liver Metabolic Genes" (2013). Pharmaceutical Sciences Faculty Publications. 197.
https://digitalcommons.cedarville.edu/pharmaceutical_sciences_publications/197
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
