CMPF, a Metabolite Formed Upon Prescription Omega-3-Acid Ethyl Ester Supplementation, Prevents and Reverses Steatosis
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-fu...
Main Authors: | , , , , , , , , , , , , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2018-01-01
|
Series: | EBioMedicine |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396417305017 |
id |
doaj-8859af43754d46f59999fc8b6184ede4 |
---|---|
record_format |
Article |
spelling |
doaj-8859af43754d46f59999fc8b6184ede42020-11-25T02:02:30ZengElsevierEBioMedicine2352-39642018-01-0127C20021310.1016/j.ebiom.2017.12.019CMPF, a Metabolite Formed Upon Prescription Omega-3-Acid Ethyl Ester Supplementation, Prevents and Reverses SteatosisKacey J. Prentice0Stacy G. Wendell1Ying Liu2Judith A. Eversley3Sonia R. Salvatore4Haneesha Mohan5Sydney L. Brandt6Andrew C. Adams7X. Serena Wang8David Wei9Garret A. FitzGerald10Timothy B. Durham11Craig D. Hammond12Kyle W. Sloop13Carsten Skarke14Francisco J. Schopfer15Michael B. Wheeler16Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, CanadaDepartment of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USADepartment of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, CanadaDepartment of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, CanadaDepartment of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USADepartment of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, CanadaDepartment of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, CanadaLilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USADepartment of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, CanadaDepartment of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, CanadaDepartment of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USALilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USALilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USALilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USADepartment of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USADepartment of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USADepartment of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, CanadaPrescription 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.http://www.sciencedirect.com/science/article/pii/S2352396417305017 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kacey J. Prentice Stacy G. Wendell Ying Liu Judith A. Eversley Sonia R. Salvatore Haneesha Mohan Sydney L. Brandt Andrew C. Adams X. Serena Wang David Wei Garret A. FitzGerald Timothy B. Durham Craig D. Hammond Kyle W. Sloop Carsten Skarke Francisco J. Schopfer Michael B. Wheeler |
spellingShingle |
Kacey J. Prentice Stacy G. Wendell Ying Liu Judith A. Eversley Sonia R. Salvatore Haneesha Mohan Sydney L. Brandt Andrew C. Adams X. Serena Wang David Wei Garret A. FitzGerald Timothy B. Durham Craig D. Hammond Kyle W. Sloop Carsten Skarke Francisco J. Schopfer Michael B. Wheeler CMPF, a Metabolite Formed Upon Prescription Omega-3-Acid Ethyl Ester Supplementation, Prevents and Reverses Steatosis EBioMedicine |
author_facet |
Kacey J. Prentice Stacy G. Wendell Ying Liu Judith A. Eversley Sonia R. Salvatore Haneesha Mohan Sydney L. Brandt Andrew C. Adams X. Serena Wang David Wei Garret A. FitzGerald Timothy B. Durham Craig D. Hammond Kyle W. Sloop Carsten Skarke Francisco J. Schopfer Michael B. Wheeler |
author_sort |
Kacey J. Prentice |
title |
CMPF, a Metabolite Formed Upon Prescription Omega-3-Acid Ethyl Ester Supplementation, Prevents and Reverses Steatosis |
title_short |
CMPF, a Metabolite Formed Upon Prescription Omega-3-Acid Ethyl Ester Supplementation, Prevents and Reverses Steatosis |
title_full |
CMPF, a Metabolite Formed Upon Prescription Omega-3-Acid Ethyl Ester Supplementation, Prevents and Reverses Steatosis |
title_fullStr |
CMPF, a Metabolite Formed Upon Prescription Omega-3-Acid Ethyl Ester Supplementation, Prevents and Reverses Steatosis |
title_full_unstemmed |
CMPF, a Metabolite Formed Upon Prescription Omega-3-Acid Ethyl Ester Supplementation, Prevents and Reverses Steatosis |
title_sort |
cmpf, a metabolite formed upon prescription omega-3-acid ethyl ester supplementation, prevents and reverses steatosis |
publisher |
Elsevier |
series |
EBioMedicine |
issn |
2352-3964 |
publishDate |
2018-01-01 |
description |
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. |
url |
http://www.sciencedirect.com/science/article/pii/S2352396417305017 |
work_keys_str_mv |
AT kaceyjprentice cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis AT stacygwendell cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis AT yingliu cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis AT judithaeversley cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis AT soniarsalvatore cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis AT haneeshamohan cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis AT sydneylbrandt cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis AT andrewcadams cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis AT xserenawang cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis AT davidwei cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis AT garretafitzgerald cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis AT timothybdurham cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis AT craigdhammond cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis AT kylewsloop cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis AT carstenskarke cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis AT franciscojschopfer cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis AT michaelbwheeler cmpfametaboliteformeduponprescriptionomega3acidethylestersupplementationpreventsandreversessteatosis |
_version_ |
1724952456356429824 |