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

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, Xiaofang Zhang, Yanjie Lu (), Xiangyu Zhong (), Baofeng Yang () and Zhenwei Pan ()
Additional contact information
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
Zhenwei Pan: Harbin Medical University

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40327-5

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