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김동현 (Dong-Hyun Kim) 저자 이메일 보기
University of Illinois at Urbana-Champaign
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조회 2217  인쇄하기 주소복사 트위터 공유 페이스북 공유 
A dysregulated acetyl/SUMO switch of FXR promotes hepatic inflammation in obesity

Dong-Hyun Kim1, Zhen Xiao2, Sanghoon Kwon1, Xiaoxiao Sun3, Daniel Ryerson1, David Tkac1, Ping Ma3, Shwu-Yuan Wu4, Cheng-Ming Chiang4, Edward Zhou5, H Eric Xu5, Jorma J Palvimo6, Lin-Feng Chen7, Byron Kemper1 and Jongsook Kim Kemper1,*

1 Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
2 Laboratory of Proteomics and Analytical Technologies, Advanced Technology Program, SAIC-Frederick, Inc., National Cancer Institute-Frederick, Frederick, MD, USA
3 Department of Statistics, University of Georgia, Athens, GA, USA
4 Simmons Comprehensive Cancer Center, Departments of Biochemistry and Pharmacology, University of Texas, Southwestern Medical Center, Dallas, TX, USA
5 Laboratory of Structure Sciences, Van Andel Research Institute, Grand Rapids, MI, USA
6 Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland
7 Department of Biochemistry, University of Illinois, Urbana, IL, USA

*Corresponding author : Jongsook Kim Kemper

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.

Keywords: acetylation; NF-κB; PIASy; steatosis; SUMO2

논문정보
- 형식: Research article
- 게재일: 2014년 11월 (BRIC 등록일 2014-11-27)
- 연구진: 국외연구진
- 분야: Genomics
광유전학의 과거, 현재와 미래[Neuron]
김윤석
발표: 김윤석 (Stanford University)
일자: 2020년 7월 30일 (목) 오후 02시 (한국시간)
언어: 한국어
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