title: Endogenous and Synthetic ABHD5 Ligands Regulate ABHD5-Perilipin Interactions and Lipolysis in Fat and Muscle.
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.
authors.affiliation: Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Sanders
authors.affiliation: Lead Identification Division, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Franck
authors.initials: F
authors.lastname: Madoux
authors.affiliation: Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Ljiljana
authors.initials: L
authors.lastname: Mladenovic
authors.affiliation: Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Huamei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Xiangqun
authors.initials: X
authors.lastname: Ye
authors.affiliation: Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Michelle
authors.initials: M
authors.lastname: Angrish
authors.affiliation: Center for Integrative Metabolic and Endocrine Research, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Emilio P
authors.initials: EP
authors.lastname: Mottillo
authors.affiliation: Institute of Environmental Health Sciences, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Caruso
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Geoff
authors.initials: G
authors.lastname: Halvorsen
authors.affiliation: Department of Chemistry, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: William R
authors.initials: WR
authors.lastname: Roush
authors.affiliation: Lead Identification Division, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Chase
authors.affiliation: Lead Identification Division, The Scripps Research Institute, Jupiter, FL 33458, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Hodder
authors.affiliation: 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: jgranne@med.wayne.edu.
authors.forename: James G
authors.initials: JG
authors.lastname: Granneman
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism*; D041721:3T3-L1 Cells; D000214:Acyl Coenzyme A / Q000378:metabolism; D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics; D006801:Humans; D008024:Ligands; D008066:Lipolysis / Q000235:genetics*; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D000070778:Perilipin-1; D000070797:Perilipin-5; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000214:Acyl Coenzyme A; D002352:Carrier Proteins; D008024:Ligands; C000602978:PLIN1 protein, human; D000070778:Perilipin-1; D000070797:Perilipin-5; D010750:Phosphoproteins; C000602979:Plin1 protein, mouse; C511805:Plin5 protein, mouse; D011506:Proteins; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C492986:Abhd5 protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases