Cell Reports (Oct 2013)
The Serine Hydrolase ABHD6 Is a Critical Regulator of the Metabolic Syndrome
- Gwynneth Thomas,
- Jenna L. Betters,
- Caleb C. Lord,
- Amanda L. Brown,
- Stephanie Marshall,
- Daniel Ferguson,
- Janet Sawyer,
- Matthew A. Davis,
- John T. Melchior,
- Lawrence C. Blume,
- Allyn C. Howlett,
- Pavlina T. Ivanova,
- Stephen B. Milne,
- David S. Myers,
- Irina Mrak,
- Vera Leber,
- Christoph Heier,
- Ulrike Taschler,
- Jacqueline L. Blankman,
- Benjamin F. Cravatt,
- Richard G. Lee,
- Rosanne M. Crooke,
- Mark J. Graham,
- Robert Zimmermann,
- H. Alex Brown,
- J. Mark Brown
Affiliations
- Gwynneth Thomas
- Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Jenna L. Betters
- Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Caleb C. Lord
- Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Amanda L. Brown
- Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Stephanie Marshall
- Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Daniel Ferguson
- Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Janet Sawyer
- Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Matthew A. Davis
- Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- John T. Melchior
- Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Lawrence C. Blume
- Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Allyn C. Howlett
- Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- Pavlina T. Ivanova
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
- Stephen B. Milne
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
- David S. Myers
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
- Irina Mrak
- Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria
- Vera Leber
- Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria
- Christoph Heier
- Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria
- Ulrike Taschler
- Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria
- Jacqueline L. Blankman
- Department of Chemical Physiology, Scripps Research Institute, La Jolla, CA 92037, USA
- Benjamin F. Cravatt
- Department of Chemical Physiology, Scripps Research Institute, La Jolla, CA 92037, USA
- Richard G. Lee
- Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
- Rosanne M. Crooke
- Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
- Mark J. Graham
- Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
- Robert Zimmermann
- Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria
- H. Alex Brown
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
- J. Mark Brown
- Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
- DOI
- https://doi.org/10.1016/j.celrep.2013.08.047
- Journal volume & issue
-
Vol. 5,
no. 2
pp. 508 – 520
Abstract
The serine hydrolase α/β hydrolase domain 6 (ABHD6) has recently been implicated as a key lipase for the endocannabinoid 2-arachidonylglycerol (2-AG) in the brain. However, the biochemical and physiological function for ABHD6 outside of the central nervous system has not been established. To address this, we utilized targeted antisense oligonucleotides (ASOs) to selectively knock down ABHD6 in peripheral tissues in order to identify in vivo substrates and understand ABHD6’s role in energy metabolism. Here, we show that selective knockdown of ABHD6 in metabolic tissues protects mice from high-fat-diet-induced obesity, hepatic steatosis, and systemic insulin resistance. Using combined in vivo lipidomic identification and in vitro enzymology approaches, we show that ABHD6 can hydrolyze several lipid substrates, positioning ABHD6 at the interface of glycerophospholipid metabolism and lipid signal transduction. Collectively, these data suggest that ABHD6 inhibitors may serve as therapeutics for obesity, nonalcoholic fatty liver disease, and type II diabetes.
