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Cullin-associated and neddylation-dissociated protein 1 (CAND1) alleviates NAFLD by reducing ubiquitinated degradation of ACAA2

Author

Listed:
  • Xiang Huang

    (Harbin Medical University)

  • Xin Liu

    (Harbin Medical University)

  • Xingda Li

    (Harbin Medical University)

  • Yang Zhang

    (Harbin Medical University)

  • Jianjun Gao

    (Surgery Second Affiliated Hospital of Harbin Medical University)

  • Ying Yang

    (Harbin Medical University)

  • Yuan Jiang

    (Sun Yat-Sen University)

  • Haiyu Gao

    (Harbin Medical University)

  • Chongsong Sun

    (Harbin Medical University)

  • Lina Xuan

    (Harbin Medical University)

  • Lexin Zhao

    (Harbin Medical University)

  • Jiahui Song

    (Harbin Medical University)

  • Hairong Bao

    (Harbin Medical University)

  • Zhiwen Zhou

    (Harbin Medical University)

  • Shangxuan Li

    (Harbin Medical University)

  • Xiaofang Zhang

    (Harbin Medical University)

  • Yanjie Lu

    (Harbin Medical University)

  • Xiangyu Zhong

    (Surgery Second Affiliated Hospital of Harbin Medical University)

  • Baofeng Yang

    (Harbin Medical University
    Chinese Academy of Medical Sciences, 2019 Research Unit 070
    Harbin Medical University)

  • Zhenwei Pan

    (Harbin Medical University
    Chinese Academy of Medical Sciences, 2019 Research Unit 070
    Harbin Medical University)

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disorder with high morbidity and mortality. The current study aims to explore the role of Cullin-associated and neddylation-dissociated protein 1 (CAND1) in the development of NAFLD and the underlying mechanisms. CAND1 is reduced in the liver of NAFLD male patients and high fat diet (HFD)-fed male mice. CAND1 alleviates palmitate (PA) induced lipid accumulation in vitro. Hepatocyte-specific knockout of CAND1 exacerbates HFD-induced liver injury in HFD-fed male mice, while hepatocyte-specific knockin of CAND1 ameliorates these pathological changes. Mechanistically, deficiency of CAND1 enhances the assembly of Cullin1, F-box only protein 42 (FBXO42) and acetyl-CoA acyltransferase 2 (ACAA2) complexes, and thus promotes the ubiquitinated degradation of ACAA2. ACAA2 overexpression abolishes the exacerbated effects of CAND1 deficiency on NAFLD. Additionally, androgen receptor binds to the −187 to −2000 promoter region of CAND1. Collectively, CAND1 mitigates NAFLD by inhibiting Cullin1/FBXO42 mediated ACAA2 degradation.

Suggested Citation

  • Xiang Huang & Xin Liu & Xingda Li & Yang Zhang & Jianjun Gao & Ying Yang & Yuan Jiang & Haiyu Gao & Chongsong Sun & Lina Xuan & Lexin Zhao & Jiahui Song & Hairong Bao & Zhiwen Zhou & Shangxuan Li & Xi, 2023. "Cullin-associated and neddylation-dissociated protein 1 (CAND1) alleviates NAFLD by reducing ubiquitinated degradation of ACAA2," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40327-5
    DOI: 10.1038/s41467-023-40327-5
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    References listed on IDEAS

    as
    1. Shuangding Wu & Wenhong Zhu & Tina Nhan & Julia I. Toth & Matthew D. Petroski & Dieter A. Wolf, 2013. "CAND1 controls in vivo dynamics of the cullin 1-RING ubiquitin ligase repertoire," Nature Communications, Nature, vol. 4(1), pages 1-9, June.
    2. Simone Cavadini & Eric S. Fischer & Richard D. Bunker & Alessandro Potenza & Gondichatnahalli M. Lingaraju & Kenneth N. Goldie & Weaam I. Mohamed & Mahamadou Faty & Georg Petzold & Rohan E. J. Beckwit, 2016. "Cullin–RING ubiquitin E3 ligase regulation by the COP9 signalosome," Nature, Nature, vol. 531(7596), pages 598-603, March.
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