2. Academic Validation
  3. Mild iron overload induces TRIP12-mediated degradation of YY1 to trigger hepatic inflammation

Mild iron overload induces TRIP12-mediated degradation of YY1 to trigger hepatic inflammation

  • Free Radic Biol Med. 2020 Dec;161:187-197. doi: 10.1016/j.freeradbiomed.2020.10.013.
Yuxiao Tang 1,  Dongyao Wang 2,  Xiaowen Niu 3,  Huiwen Wu 4,  Jianxin Yang 1,  Yinyin Zhang 1,  Shangjin Song 5,  Diya Lv 6,  Yifeng Chai 6,  Hongtao Lu 1,  Hui Shen 7,  Chen Ling 8,  Min Li 9
Affiliations

Affiliations

  • 1 Department of Nutrition, Second Military Medical University, Shanghai, China.
  • 2 School of Pharmacy, Second Military Medical University, Shanghai, China; Faculty of Pharmacy, Shanghai University, Shanghai, China.
  • 3 Shanghai Dermatology Hospital, Tongji University, Shanghai, China.
  • 4 Department of Nutrition, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China.
  • 5 School of Traditional Chinese Medicine & Changzheng Hospital, Second Military Medical University, Shanghai, China.
  • 6 School of Pharmacy, Second Military Medical University, Shanghai, China.
  • 7 Department of Nutrition, Second Military Medical University, Shanghai, China. Electronic address: shenhui@smmu.edu.cn.
  • 8 State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China; Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA. Electronic address: lingchen@peds.ufl.edu.
  • 9 Department of Nutrition, Second Military Medical University, Shanghai, China; Institute of International Medical Science and Technology, Sanda University, Shanghai, China. Electronic address: limin@smmu.edu.cn.
PMID: 33080340 DOI: 10.1016/j.freeradbiomed.2020.10.013
Abstract

Increasing populations are found to bear mild hepatic iron overload (HIO) due to unhealthy lifestyles, metabolic diseases, etc., whether this mild but chronic HIO induces hepatic inflammation is unknown. In the present study, mice receiving a 12-months 0.3% dextran-iron diet show mild HIO with no detectable oxidative damages in the liver but have infiltrated macrophages and increased IL-6, TNFα, AST and ALT since 6-months. The HNF4α/miR-122/CCL2 pathway, identified by our previous studies to induce macrophages infiltration, is initiated by chronic mild HIO. After excluding the role of DNA methylation, a modified transcription factor microarray is applied to find that transcription factor YY1 is responsible for HIO-decreased HNF4α expression. Then the E3 ubiquitin ligase TRIP12 is identified by an immunoprecipitation coupled LC-MS/MS and proved to bind and ubiquitinate YY1, leading to its degradation. The overexpression or silence of YY1 in the liver regulates the HNF4α/miR-122/CCL2 pathway. More importantly, YY1 overexpression alleviates chronic mild HIO induced hepatic inflammatory responses. In conclusion, these results elucidate an oxidative-stress-independent, TRIP12/YY1/HNF4α/miR-122/CCL2 pathway of chronic mild HIO inducing hepatic inflammation, implying that effective measures in addition to antioxidants are needed for individuals at the risk of chronic mild HIO.

Keywords

Chronic mild iron overload; E3 ubiquitin ligase TRIP12; Hepatic inflammation; Transcription factor YY1.

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