ArticleThe Journal of biological chemistry2013
Bile acid signal-induced phosphorylation of small heterodimer partner by protein kinase Cζ is critical for epigenomic regulation of liver metabolic genes.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 41 citations in OpenAlex.
- The role of FGF19-FGFR4 signaling pathway in liver health and disease: Guardian or destroyer.Genes & diseases · 2026Review
- Microbiota-Derived Metabolites in the Epigenetic Regulation of Redox Homeostasis.Antioxidants (Basel, Switzerland) · 2026Review
- Enhanced nuclear localization of small heterodimer partner in metabolic dysfunction-associated steatohepatitis.JHEP reports : innovation in hepatology · 2026Article
- Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development.Pharmacological reviews · 2024Review
- Feeding activates FGF15-SHP-TFEB-mediated lipophagy in the gut.The EMBO journal · 2022Article
- Deletion of Intestinal SHP Impairs Short-term Response to Cholic Acid Challenge in Male Mice.Endocrinology · 2021Article
- The Nuclear Farnesoid X Receptor Reduces p53 Ubiquitination and Inhibits Cervical Cancer Cell Proliferation.Frontiers in cell and developmental biology · 2021Article
- Intestinal FGF15/19 physiologically repress hepatic lipogenesis in the late fed-state by activating SHP and DNMT3A.Nature communications · 2020Article
- A novel role for farnesoid X receptor in the bile acid-mediated intestinal glucose homeostasis.Journal of cellular and molecular medicine · 2020Article
- MicroRNA-210 Promotes Bile Acid-Induced Cholestatic Liver Injury by Targeting Mixed-Lineage Leukemia-4 Methyltransferase in Mice.Hepatology (Baltimore, Md.) · 2020Article
- Up to date on cholesterol 7 alpha-hydroxylase (CYP7A1) in bile acid synthesis.Liver research (Beijing, China) · 2020Article
- Determinants of Cytochrome P450 2D6 mRNA Levels in Healthy Human Liver Tissue.Clinical and translational science · 2019Article
- Small Heterodimer Partner and Fibroblast Growth Factor 19 Inhibit Expression of NPC1L1 in Mouse Intestine and Cholesterol Absorption.Gastroenterology · 2019Article
- Postprandial FGF19-induced phosphorylation by Src is critical for FXR function in bile acid homeostasis.Nature communications · 2018Article
- Hepatocyte nuclear receptor SHP suppresses inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis.The Journal of biological chemistry · 2018Article
- AhR and SHP regulate phosphatidylcholine and S-adenosylmethionine levels in the one-carbon cycle.Nature communications · 2018Article
- Obesity-Linked Phosphorylation of SIRT1 by Casein Kinase 2 Inhibits Its Nuclear Localization and Promotes Fatty Liver.Molecular and cellular biology · 2017Article
- Bile acids as global regulators of hepatic nutrient metabolism.Liver research (Beijing, China) · 2017Article
- Critical role of RanBP2-mediated SUMOylation of Small Heterodimer Partner in maintaining bile acid homeostasis.Nature communications · 2016Article
- Article
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
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.
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