S-acylation of ATGL is required for lipid droplet homoeostasis in hepatocytes

  • Nat Metab. 2024 Aug;6(8):1549-1565. doi: 10.1038/s42255-024-01085-w.
Yuping Zheng  #  1 ,  Jishun Chen  #  2 ,  Vinitha Macwan  #  3 ,  Charneal L Dixon  #  4  5 ,  Xinran Li  6 ,  Shengjie Liu  7 ,  Yuyun Yu  1 ,  Pinglong Xu  8 ,  Qiming Sun  1 ,  Qi Hu  7 ,  Wei Liu  9 ,  Brian Raught  10 ,  Gregory D Fairn  11  12 ,  Dante Neculai  13
Affiliations
  • 1. Center for Metabolism Research, The Fourth Affiliated Hospital of School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China.
  • 2. Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, China.
  • 3. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • 4. Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University Health Network, Toronto, Ontario, Canada.
  • 5. Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
  • 6. ZJU-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou, China.
  • 7. Westlake AI Therapeutics Lab, Westlake Laboratory of Life Sciences and Biomedicine, School of Life Sciences, Westlake University, Hangzhou, China.
  • 8. Life Science Institute, Zhejiang University, Hangzhou, China.
  • 9. Center for Metabolism Research, The Fourth Affiliated Hospital of School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China. [email protected].
  • 10. Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada. [email protected].
  • 11. Keenan Research Centre for Biomedical Science, St. Michael's Hospital, University Health Network, Toronto, Ontario, Canada. [email protected].
  • 12. Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada. [email protected].
  • 13. Center for Metabolism Research, The Fourth Affiliated Hospital of School of Medicine and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, China. [email protected].
  • # Contributed equally.
PMID: 39143266 DOI: 10.1038/s42255-024-01085-w
Abstract

Lipid droplets (LDs) are organelles specialized in the storage of neutral lipids, Cholesterol esters and triglycerides, thereby protecting cells from the toxicity of excess lipids while allowing for the mobilization of lipids in times of nutrient deprivation. Defects in LD function are associated with many diseases. S-acylation mediated by zDHHC acyltransferases modifies thousands of proteins, yet the physiological impact of this post-translational modification on individual proteins is poorly understood. Here, we show that zDHHC11 regulates LD catabolism by modifying adipose triacylglyceride Lipase (ATGL), the rate-limiting enzyme of lipolysis, both in hepatocyte cultures and in mice. zDHHC11 S-acylates ATGL at cysteine 15. Preventing the S-acylation of ATGL renders it catalytically inactive despite proper localization. Overexpression of zDHHC11 reduces LD size, whereas its elimination enlarges LDs. Mutating ATGL cysteine 15 phenocopies zDHHC11 loss, causing LD accumulation, defective lipolysis and lipophagy. Our results reveal S-acylation as a mode of regulation of ATGL function and LD homoeostasis. Modulating this pathway may offer therapeutic potential for treating diseases linked to defective lipolysis, such as fatty liver disease.

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