Phosphorylation of 17β-hydroxysteroid dehydrogenase 13 at serine 33 attenuates nonalcoholic fatty liver disease in mice

Wen Su (), Sijin Wu, Yongliang Yang, Yanlin Guo, Haibo Zhang, Jie Su, Lei Chen, Zhuo Mao, Rongfeng Lan, Rong Cao, Chunjiong Wang, Hu Xu, Cong Zhang, Sha Li, Min Gao, Xiaocong Chen, Zhiyou Zheng, Bing Wang, Yi’ao Liu, Zuojun Liu, Zimei Wang, Baohua Liu, Xinmin Fan, Xiaoyan Zhang () and Youfei Guan ()
Additional contact information
Wen Su: Shenzhen University
Sijin Wu: Chinese Academy of Sciences
Yongliang Yang: Dalian University of Technology
Yanlin Guo: East China Normal University
Haibo Zhang: Dalian Medical University
Jie Su: Shenzhen University
Lei Chen: Shenzhen University
Zhuo Mao: Shenzhen University Health Science Center, Shenzhen University
Rongfeng Lan: Shenzhen University Health Science Center, Shenzhen University
Rong Cao: The First Affiliated Hospital of Shenzhen University
Chunjiong Wang: Tianjin Medical University
Hu Xu: Dalian Medical University
Cong Zhang: Dalian Medical University
Sha Li: Hebei University of Engineering
Min Gao: Shenzhen University Health Science Center, Shenzhen University
Xiaocong Chen: Shenzhen University Health Science Center, Shenzhen University
Zhiyou Zheng: Shenzhen University Health Science Center, Shenzhen University
Bing Wang: Dalian Medical University
Yi’ao Liu: Shenzhen University Health Science Center, Shenzhen University
Zuojun Liu: Shenzhen University Health Science Center, Shenzhen University
Zimei Wang: Shenzhen University Health Science Center, Shenzhen University
Baohua Liu: Shenzhen University Health Science Center, Shenzhen University
Xinmin Fan: Shenzhen University
Xiaoyan Zhang: East China Normal University
Youfei Guan: Dalian Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract 17β-hydroxysteroid dehydrogenase-13 is a hepatocyte-specific, lipid droplet-associated protein. A common loss-of-function variant of HSD17B13 (rs72613567: TA) protects patients against non-alcoholic fatty liver disease with underlying mechanism incompletely understood. In the present study, we identify the serine 33 of 17β-HSD13 as an evolutionally conserved PKA target site and its phosphorylation facilitates lipolysis by promoting its interaction with ATGL on lipid droplets. Targeted mutation of Ser33 to Ala (S33A) decreases ATGL-dependent lipolysis in cultured hepatocytes by reducing CGI-58-mediated ATGL activation. Importantly, a transgenic knock-in mouse strain carrying the HSD17B13 S33A mutation (HSD17B1333A/A) spontaneously develops hepatic steatosis with reduced lipolysis and increased inflammation. Moreover, Hsd17B1333A/A mice are more susceptible to high-fat diet-induced nonalcoholic steatohepatitis. Finally, we find reproterol, a potential 17β-HSD13 modulator and FDA-approved drug, confers a protection against nonalcoholic steatohepatitis via PKA-mediated Ser33 phosphorylation of 17β-HSD13. Therefore, targeting the Ser33 phosphorylation site could represent a potential approach to treat NASH.

Date: 2022
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DOI: 10.1038/s41467-022-34299-1

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