Malonylation of Acetyl-CoA carboxylase 1 promotes hepatic steatosis and is attenuated by ketogenic diet in NAFLD
Huanyi Cao,
Qingxian Cai,
Wanrong Guo,
Qiao Su,
Hancheng Qin,
Tian Wang,
Yingxin Xian,
Longyi Zeng,
Mengyin Cai,
Haixia Guan,
Sifan Chen,
Hua Liang,
Fen Xu
Affiliations
Huanyi Cao
Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, P.R. China; Department of Endocrinology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, P.R. China
Qingxian Cai
Department of Hepatopathy, the Third People’s Hospital of Shenzhen, the Second Affiliated Hospital of Southern University of Science and Technology, Shenzhen 518112, P.R. China
Wanrong Guo
Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, P.R. China
Qiao Su
Animal Experiment Center, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, P.R. China
Hancheng Qin
Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, P.R. China
Tian Wang
Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, P.R. China
Yingxin Xian
Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, P.R. China
Longyi Zeng
Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, P.R. China
Mengyin Cai
Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, P.R. China
Haixia Guan
Department of Endocrinology, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou 510080, P.R. China
Sifan Chen
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China; Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, P.R. China
Hua Liang
Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, P.R. China; Corresponding author
Fen Xu
Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, P.R. China; Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, P.R. China; Corresponding author
Summary: Protein post-translational modifications (PTMs) participate in important bioactive regulatory processes and therefore can help elucidate the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Here, we investigate the involvement of PTMs in ketogenic diet (KD)-improved fatty liver by multi-omics and reveal a core target of lysine malonylation, acetyl-coenzyme A (CoA) carboxylase 1 (ACC1). ACC1 protein levels and Lys1523 malonylation are significantly decreased by KD. A malonylation-mimic mutant of ACC1 increases its enzyme activity and stability to promote hepatic steatosis, whereas the malonylation-null mutant upregulates the ubiquitination degradation of ACC1. A customized Lys1523ACC1 malonylation antibody confirms the increased malonylation of ACC1 in the NAFLD samples. Overall, the lysine malonylation of ACC1 is attenuated by KD in NAFLD and plays an important role in promoting hepatic steatosis. Malonylation is critical for ACC1 activity and stability, highlighting the anti-malonylation effect of ACC1 as a potential strategy for treating NAFLD.
