title: A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity.
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 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.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick, Inc. National Cancer Institute-Frederick, Frederick, MD, USA.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Xiao
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Sanghoon
authors.initials: S
authors.lastname: Kwon
authors.affiliation: Department of Statistics, University of Georgia, Athens, GA, USA.
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ryerson
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: David
authors.initials: D
authors.lastname: Tkac
authors.affiliation: Department of Statistics, University of Georgia, Athens, GA, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Ma
authors.affiliation: Simmons Comprehensive Cancer Center, Departments of Biochemistry and Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Shwu-Yuan
authors.initials: SY
authors.lastname: Wu
authors.affiliation: Simmons Comprehensive Cancer Center, Departments of Biochemistry and Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chiang
authors.affiliation: Laboratory of Structure Sciences, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Zhou
authors.affiliation: Laboratory of Structure Sciences, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: H Eric
authors.initials: HE
authors.lastname: Xu
authors.affiliation: Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Jorma J
authors.initials: JJ
authors.lastname: Palvimo
authors.affiliation: Department of Biochemistry, University of Illinois, Urbana, IL, USA.
authors.forename: Lin-Feng
authors.initials: LF
authors.lastname: Chen
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
authors.forename: Byron
authors.initials: B
authors.lastname: Kemper
authors.affiliation: Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA jongsook@illinois.edu.
authors.forename: Jongsook Kim
authors.initials: JK
authors.lastname: Kemper
mesh_terms: D000107:Acetylation; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D007249:Inflammation / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008107:Liver Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000150:complications* / Q000503:physiopathology; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D040901:Proteomics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D025841:Small Ubiquitin-Related Modifier Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation; D053719:Tandem Mass Spectrometry; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D025841:Small Ubiquitin-Related Modifier Proteins; D000099150:Receptor, Farnesoid X-Activated; C515972:SUMO2 protein, mouse
keywords: NF‐κB; PIASy; SUMO2; acetylation; steatosis