2. Academic Validation
  3. Cullin-associated and neddylation-dissociated protein 1 (CAND1) alleviates NAFLD by reducing ubiquitinated degradation of ACAA2

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

  • Nat Commun. 2023 Aug 1;14(1):4620. doi: 10.1038/s41467-023-40327-5.
Xiang Huang # 1,  Xin Liu # 2,  Xingda Li # 3,  Yang Zhang # 1,  Jianjun Gao 4,  Ying Yang 1,  Yuan Jiang 5,  Haiyu Gao 1,  Chongsong Sun 1,  Lina Xuan 1,  Lexin Zhao 1,  Jiahui Song 1,  Hairong Bao 1,  Zhiwen Zhou 1,  Shangxuan Li 1,  Xiaofang Zhang 1,  Yanjie Lu 6,  Xiangyu Zhong 7,  Baofeng Yang 8 9 10,  Zhenwei Pan 11 12 13
Affiliations

Affiliations

  • 1 Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Disease, Key Laboratory of Cardiovascular Research. Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150086, P. R. China.
  • 2 The Department of Histology and Embryology, Harbin Medical University, Harbin, 150086, China.
  • 3 Department of Pharmacy at the Second Affiliated Hospital, and Department of Pharmacology at College of Pharmacy (The Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, 150086, China.
  • 4 The Department of Hepatopancreatobility, Surgery Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
  • 5 Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
  • 6 Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Disease, Key Laboratory of Cardiovascular Research. Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150086, P. R. China. yjlu@hrbmu.edu.cn.
  • 7 The Department of Hepatopancreatobility, Surgery Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China. zhongxiangyu@hrbmu.edu.cn.
  • 8 Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Disease, Key Laboratory of Cardiovascular Research. Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150086, P. R. China. yangbf@ems.hrbmu.edu.cn.
  • 9 Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, 2019 Research Unit 070, Harbin, Heilongjiang, 150086, P. R. China. yangbf@ems.hrbmu.edu.cn.
  • 10 State Key Laboratory, Harbin Medical University, Harbin, 150086, China. yangbf@ems.hrbmu.edu.cn.
  • 11 Department of Pharmacology (National Key Laboratory of Frigid Zone Cardiovascular Disease, Key Laboratory of Cardiovascular Research. Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang, 150086, P. R. China. panzw@ems.hrbmu.edu.cn.
  • 12 Research Unit of Noninfectious Chronic Diseases in Frigid Zone, Chinese Academy of Medical Sciences, 2019 Research Unit 070, Harbin, Heilongjiang, 150086, P. R. China. panzw@ems.hrbmu.edu.cn.
  • 13 Key Laboratory of Cell Transplantation, The First Affiliated Hospital, Harbin Medical University, Harbin, 150086, China. panzw@ems.hrbmu.edu.cn.
  • # Contributed equally.
PMID: 37528093 DOI: 10.1038/s41467-023-40327-5
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.

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