A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity
Open accessAbstract
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 RXRα, so that SUMO2-modified FXR was selectively recruited to and trans-repressed inflammatory genes without affecting FXR/RXRα 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.
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SUMOylation of FXR negatively regulated expression of its target genes, including SHP, BSEP, and OSTB.
“In line with the current results, others demonstrated that SUMOylation of FXR negatively regulated expression of its target genes, including SHP, BSEP, and OSTB55.”
From SUMOylation inhibitors synergize with FXR agonists in combating liver fibrosis (2020) · cites this paper as [55]
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References 47 · Cited by 126
- Authors
- Kim, D., Xiao, Z., Kwon, S., Sun, X., Ryerson, D., Tkac, D., Ma, P., Wu, S., Chiang, C., Zhou, E., Xu, H. E., Palvimo, J. J., Chen, L., Kemper, B., & Kemper, J. K.
- Affiliations
- University of Illinois Urbana-Champaign (US)
- Frederick National Laboratory for Cancer Research (US)
- University of Georgia (US)
- Harold C. Simmons Comprehensive Cancer Center (US)
- Van Andel Institute (US)
- University of Eastern Finland (FI)
- Corresponding author
- Kemper, Jongsook Kim
- ORCID
- Venue
- The EMBO Journal
- Published
- 2014-11-25
- Volume
- 34
- Issue
- 2
- Pages
- 184-199
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC4337071
- OpenAlex
- W2125876853
- Cited by
- 126
- References
- 47
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 8 · 2023: 11 · 2022: 17 · 2021: 14 · 2020: 12 · 2019: 10 · 2018: 11 · 2017: 14 · 2016: 11 · 2015: 6
- FWCI
- 7.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AHA post‐doctoral fellowship (14POST20420006)
- NSF (DMS‐1440037, DMS‐1228288)
- NIH (CA103867, DK62777, DK95842)
- CPRIT (RP110471, RP140367)
- Welch Foundation (I‐1805)
- Academy of Finland
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- farnesoid X receptor, SUMOylation, SUMO2, PIASy, obesity, liver inflammation, NF-κB, RXRα, macrophage infiltration, insulin signaling, impaired glucose tolerance, transrepression, diet-induced obesity
- MeSH terms
- Receptor, Farnesoid X-Activated, Acetylation, Amino Acid Sequence, Animals, Gene Expression Regulation, Immunoenzyme Techniques, Inflammation, Liver Diseases, Male, Mice, Inbred C57BL, Mice, Obese, Molecular Sequence Data, Obesity, Protein Conformation, Protein Processing, Post-Translational, RNA, Messenger, Blotting, Western, Cytokines, NF-kappa B, Sequence Homology, Amino Acid, Receptors, Cytoplasmic and Nuclear, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, Electrophoretic Mobility Shift Assay, Small Ubiquitin-Related Modifier Proteins, Proteomics, Immunoprecipitation, Mice, Tandem Mass Spectrometry, Sumoylation, Real-Time Polymerase Chain Reaction
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