Endogenous and Synthetic ABHD5 Ligands Regulate ABHD5-Perilipin Interactions and Lipolysis in Fat and Muscle

  • Cell Metab. 2015 Nov 3;22(5):851-60. doi: 10.1016/j.cmet.2015.08.023.
Matthew A Sanders  1 ,  Franck Madoux  2 ,  Ljiljana Mladenovic  1 ,  Huamei Zhang  1 ,  Xiangqun Ye  1 ,  Michelle Angrish  1 ,  Emilio P Mottillo  1 ,  Joseph A Caruso  3 ,  Geoff Halvorsen  4 ,  William R Roush  4 ,  Peter Chase  2 ,  Peter Hodder  2 ,  James G Granneman  5
Affiliations
  • 1. Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI 48201, USA.
  • 2. Lead Identification Division, The Scripps Research Institute, Jupiter, FL 33458, USA.
  • 3. Institute of Environmental Health Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.
  • 4. Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA.
  • 5. Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI 48201, USA; John Dingell Veterans Administration Medical Center, Detroit, MI 48201, USA. Electronic address: [email protected].
PMID: 26411340 DOI: 10.1016/j.cmet.2015.08.023
Abstract

Fat and muscle lipolysis involves functional interactions of adipose triglyceride Lipase (ATGL), α-β hydrolase domain-containing protein 5 (ABHD5), and tissue-specific perilipins 1 and 5 (PLIN1 and PLIN5). ABHD5 potently activates ATGL, but this lipase-promoting activity is suppressed when ABHD5 is bound to PLIN proteins on lipid droplets. In adipocytes, protein kinase A (PKA) phosphorylation of PLIN1 rapidly releases ABHD5 to activate ATGL, but mechanisms for rapid regulation of PLIN5-ABHD5 interaction in muscle are unknown. Here, we identify synthetic ligands that release ABHD5 from PLIN1 or PLIN5 without PKA activation and rapidly activate adipocyte and muscle lipolysis. Molecular imaging and affinity probe labeling demonstrated that ABHD5 is directly targeted by these synthetic ligands and additionally revealed that ABHD5-PLIN interactions are regulated by endogenous ligands, including long-chain acyl-CoA. Our results reveal a new locus of lipolysis control and suggest ABHD5 ligands might be developed into novel therapeutics that directly promote fat catabolism.

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