3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF) prevents high fat diet-induced insulin resistance via maintenance of hepatic lipid homeostasis.

AIM: Omega-3 fatty acid ethyl ester supplements, available by prescription, are common in the treatment of dyslipidaemia in humans. Recent studies show that 3-carboxy-4-methyl-5-propyl-2-furanpropanoic acid (CMPF), a metabolite formed from fish oil supplementation, was able to prevent and reverse high fat diet (HFD)-induced fatty liver in mice. In the present study, we investigated the underlying molecular mechanisms responsible for CMPF's hepatic lipid-lowering effects. MATERIALS AND METHODS: CD1 male mice were i.p. injected with CMPF (dosage, 6 mg/kg) for 7 days, followed by 5 weeks of a 60% HFD to induce a fatty liver phenotype. Metabolic parameters, liver morphology, lipid content, protein expression and microarray analysis were assessed. We also utilized primary hepatocytes, an in vitro model, to further investigate the direct effects of CMPF on hepatic lipid utilization and biosynthesis. RESULTS: CMPF-treated mice display enhanced hepatic lipid clearance while hepatic lipid storage is prevented, thereby protecting against liver lipid accumulation and development of HFD-induced hepatic insulin resistance. Mechanistically, as CMPF enters the liver, it acts as an allosteric acetyl-coA carboxylase (ACC) inhibitor, which directly induces both fatty acid oxidation and hepatic production of fibroblast growth factor 21 (FGF21). A feed-back loop is initiated by CMPF, which exists between ACC inhibition, fatty acid oxidation and production of FGF21. As a consequence, an adaptive decrease in Insig2/SREBP-1c/FAS protein expression results in priming of the liver to prevent a HFD-induced fatty liver phenotype. CONCLUSION: CMPF is a potential driver of hepatic lipid metabolism, preventing diet-induced hepatic lipid deposition and insulin resistance in the long term.

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-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.