2. Academic Validation
  3. Phosphorylation of 17β-hydroxysteroid dehydrogenase 13 at serine 33 attenuates nonalcoholic fatty liver disease in mice

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

  • Nat Commun. 2022 Nov 2;13(1):6577. doi: 10.1038/s41467-022-34299-1.
Wen Su 1 2,  Sijin Wu 3,  Yongliang Yang 4,  Yanlin Guo 5,  Haibo Zhang 6,  Jie Su 7 8,  Lei Chen 7 8,  Zhuo Mao 8,  Rongfeng Lan 8,  Rong Cao 9,  Chunjiong Wang 10,  Hu Xu 6,  Cong Zhang 6,  Sha Li 11,  Min Gao 8,  Xiaocong Chen 8,  Zhiyou Zheng 8,  Bing Wang 6,  Yi'ao Liu 8,  Zuojun Liu 8,  Zimei Wang 8,  Baohua Liu 8,  Xinmin Fan 7 8,  Xiaoyan Zhang 12,  Youfei Guan 13 14
Affiliations

Affiliations

  • 1 Department of Pathophysiology, Shenzhen University, Shenzhen, 518060, China. [email protected].
  • 2 Shenzhen University Health Science Center, Shenzhen University, Shenzhen, 518060, China. [email protected].
  • 3 State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116024, China.
  • 4 Laboratoy of Innovative Drug Discovery, School of Bioengineering, Dalian University of Technology, Dalian, 116023, China.
  • 5 Health Science Center, East China Normal University, Shanghai, 200241, China.
  • 6 Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China.
  • 7 Department of Pathophysiology, Shenzhen University, Shenzhen, 518060, China.
  • 8 Shenzhen University Health Science Center, Shenzhen University, Shenzhen, 518060, China.
  • 9 Department of Nephrology, The First Affiliated Hospital of Shenzhen University, Shenzhen, 518035, China.
  • 10 Department of Physiology and Pathophysiology, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Tianjin Medical University, Tianjin, China.
  • 11 Medical College, Hebei University of Engineering, Handan, China.
  • 12 Health Science Center, East China Normal University, Shanghai, 200241, China. [email protected].
  • 13 Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, 116044, China. [email protected].
  • 14 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Dalian Medical University, Dalian, 116044, China. [email protected].
PMID: 36323699 DOI: 10.1038/s41467-022-34299-1
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.

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