A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity

Dong Hyun Kim, Zhen Xiao, Sanghoon Kwon, Xiaoxiao Sun, Daniel Ryerson, David Tkac, Ping Ma, Shwu Yuan Wu, Cheng Ming Chiang, Edward Zhou, H. Eric Xu, Jorma J. Palvimo, Lin Feng Chen, Byron Kemper, Jongsook Kim Kemper

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

Acetylation of transcriptional regulators is normally dynamically regulated by nutrient status but is often persistently elevated in nutrient-excessive obesity conditions. We investigated the functional consequences of such aberrantly elevated acetylation of the nuclear receptor FXR as a model. Proteomic studies identified K217 as the FXR acetylation site in diet-induced obese mice. In vivo studies utilizing acetylation-mimic and acetylation-defective K217 mutants and gene expression profiling revealed that FXR acetylation increased proinflammatory gene expression, macrophage infiltration, and liver cytokine and triglyceride levels, impaired insulin signaling, and increased glucose intolerance. Mechanistically, acetylation of FXR blocked its interaction with the SUMO ligase PIASy and inhibited SUMO2 modification at K277, resulting in activation of inflammatory genes. SUMOylation of agonist-activated FXR increased its interaction with NF-κB but blocked that with RXRa, so that SUMO2-modified FXR was selectively recruited to and trans-repressed inflammatory genes without affecting FXR/RXRa target genes. A dysregulated acetyl/SUMO switch of FXR in obesity may serve as a general mechanism for diminished anti-inflammatory response of other transcriptional regulators and provide potential therapeutic and diagnostic targets for obesity-related metabolic disorders.

Original languageEnglish (US)
Pages (from-to)184-199
Number of pages16
JournalEMBO Journal
Volume34
Issue number2
DOIs
StatePublished - Jan 14 2015

Keywords

  • Acetylation
  • NF-κB
  • PIASy
  • SUMO2
  • Steatosis

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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  • Cite this

    Kim, D. H., Xiao, Z., Kwon, S., Sun, X., Ryerson, D., Tkac, D., Ma, P., Wu, S. Y., Chiang, C. M., Zhou, E., Xu, H. E., Palvimo, J. J., Chen, L. F., Kemper, B., & Kemper, J. K. (2015). A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity. EMBO Journal, 34(2), 184-199. https://doi.org/10.15252/embj.201489527