Branched Fatty Acid Esters of Hydroxy Fatty Acids Are Preferred Substrates of the MODY8 Protein Carboxyl Ester Lipase

  • Biochemistry. 2016 Aug 23;55(33):4636-41. doi: 10.1021/acs.biochem.6b00565.
Matthew J Kolar  1 ,  Siddhesh S Kamat  2 ,  William H Parsons  2 ,  Edwin A Homan  3 ,  Tim Maher  3 ,  Odile D Peroni  4 ,  Ismail Syed  4 ,  Karianne Fjeld  5  6 ,  Anders Molven  7  8 ,  Barbara B Kahn  4 ,  Benjamin F Cravatt  2 ,  Alan Saghatelian  1
Affiliations
  • 1. Peptide Biology Laboratories, Helmsley Center for Genomic Medicine, Salk Institute for Biological Studies , La Jolla, California 92037, United States.
  • 2. Department of Chemical Physiology, Skaggs Institute of Chemical Biology, The Scripps Research Institute , La Jolla, California 92037, United States.
  • 3. Department of Chemistry and Chemical Biology, Harvard University , Cambridge, Massachusetts 02138, United States.
  • 4. Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School , Boston, Massachusetts 02215, United States.
  • 5. KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen , N-5021 Bergen, Norway.
  • 6. Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital , N-5021 Bergen, Norway.
  • 7. Gade Laboratory for Pathology, Department of Clinical Medicine, University of Bergen , N-5021 Bergen, Norway.
  • 8. Department of Pathology, Haukeland University Hospital , N-5021 Bergen, Norway.
PMID: 27509211 DOI: 10.1021/acs.biochem.6b00565
Abstract

A recently discovered class of endogenous mammalian Lipids, branched fatty acid esters of Hydroxy Fatty Acids (FAHFAs), possesses anti-diabetic and anti-inflammatory activities. Here, we identified and validated carboxyl ester Lipase (CEL), a pancreatic enzyme hydrolyzing cholesteryl esters and other dietary Lipids, as a FAHFA hydrolase. Variants of CEL have been linked to maturity-onset diabetes of the young, type 8 (MODY8), and to chronic Pancreatitis. We tested the FAHFA hydrolysis activity of the CEL MODY8 variant and found a modest increase in activity as compared with that of the normal enzyme. Together, the data suggest that CEL might break down dietary FAHFAs.