2. Academic Validation
  3. CMPF, a Metabolite Formed Upon Prescription Omega-3-Acid Ethyl Ester Supplementation, Prevents and Reverses Steatosis

CMPF, a Metabolite Formed Upon Prescription Omega-3-Acid Ethyl Ester Supplementation, Prevents and Reverses Steatosis

  • EBioMedicine. 2018 Jan:27:200-213. doi: 10.1016/j.ebiom.2017.12.019.
Kacey J Prentice 1,  Stacy G Wendell 2,  Ying Liu 1,  Judith A Eversley 1,  Sonia R Salvatore 2,  Haneesha Mohan 1,  Sydney L Brandt 1,  Andrew C Adams 3,  X Serena Wang 1,  David Wei 1,  Garret A FitzGerald 4,  Timothy B Durham 3,  Craig D Hammond 3,  Kyle W Sloop 3,  Carsten Skarke 5,  Francisco J Schopfer 6,  Michael B Wheeler 7
Affiliations

Affiliations

  • 1 Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  • 2 Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA.
  • 3 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA.
  • 4 Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 5 Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: cskarke@pennmedicine.upenn.edu.
  • 6 Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: fjs2@pitt.edu.
  • 7 Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Electronic address: michael.wheeler@utoronto.ca.
PMID: 29290411 DOI: 10.1016/j.ebiom.2017.12.019
Abstract

Prescription ω-3 fatty acid ethyl ester supplements are commonly used for the treatment of hypertriglyceridemia. However, the metabolic profile and effect of the metabolites formed by these treatments remain unknown. Here we utilized unbiased metabolomics to identify 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) as a significant metabolite of the ω-3-acid ethyl ester prescription Lovaza™ in humans. Administration of CMPF to mice before or after high-fat diet feeding at exposures equivalent to those observed in humans increased whole-body lipid metabolism, improved Insulin sensitivity, increased beta-oxidation, reduced lipogenic gene expression, and ameliorated steatosis. Mechanistically, we find that CMPF acutely inhibits ACC activity, and induces long-term loss of SREBP1c and ACC1/2 expression. This corresponds to an induction of FGF21, which is required for long-term steatosis protection, as FGF21KO mice are refractory to the improved metabolic effects. Thus, CMPF treatment in mice parallels the effects of human Lovaza™ supplementation, revealing that CMPF may contribute to the improved metabolic effects observed with ω-3 fatty acid prescriptions.

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