Dietary eicosapentaenoic acid supplementation accentuates hepatic triglyceride accumulation in mice with impaired fatty acid oxidation capacity |
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Authors: | Zhen-Yu Du,Tao Ma,Bjø rn Liaset,Alison H. Keenan,Pedro Araujo,Erik-Jan Lock,Laurent Demizieux,Pascal Degrace,Livar Frø yland,Karsten Kristiansen,Lise Madsen |
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Affiliation: | 1. School of Life Science, East China Normal University, 200241 Shanghai, China;2. National Institute of Nutrition and Seafood Research (NIFES), 5817 Bergen, Norway;3. Department of Biology, University of Copenhagen, 2200 Copenhagen, Denmark;4. UMR 866, INSERM-UB, Faculté des Sciences Gabriel, 21000 Dijon, France |
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Abstract: | Reduced mitochondrial fatty acid (FA) β-oxidation can cause accumulation of triglyceride in liver, while intake of eicosapentaenoic acid (EPA) has been recommended as a promising novel therapy to decrease hepatic triglyceride content. However, reduced mitochondrial FA β-oxidation also facilitates accumulation of EPA. To investigate the interplay between EPA administration, mitochondrial activity and hepatic triglyceride accumulation, we investigated the effects of EPA administration to carnitine-deficient mice with impaired mitochondrial FA β-oxidation. C57BL/6J mice received a high-fat diet supplemented or not with 3% EPA in the presence or absence of 500 mg mildronate/kg/day for 10 days. Liver mitochondrial and peroxisomal oxidation, lipid classes and FA composition were determined. Histological staining was performed and mRNA level of genes related to lipid metabolism and inflammation in liver and adipose tissue was determined. Levels of pro-inflammatory eicosanoids and cytokines were measured in plasma. The results showed that mildronate treatment decreased hepatic carnitine concentration and mitochondrial FA β-oxidation and induced severe triglyceride accumulation accompanied by elevated systemic inflammation. Surprisingly, inclusion of EPA in the diet exacerbated the mildronate-induced triglyceride accumulation. This was accompanied by a considerable increase of EPA accumulation while decreased total n-3/n-6 ratio in liver. However, inclusion of EPA in the diet attenuated the mildronate-induced mRNA expression of inflammatory genes in adipose tissue. Taken together, dietary supplementation with EPA exacerbated the triglyceride accumulation induced by impaired mitochondrial FA β-oxidation. Thus, further thorough evaluation of the potential risk of EPA supplementation as a therapy for NAFLD associated with impaired mitochondrial FA oxidation is warranted. |
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Keywords: | ACC, acetyl-coenzyme A carboxylases ACO, acetyl-coenzyme A oxidase ALT, alanine aminotransferase APC, adipocyte AST, aspartate aminotransferase ATGL, adipose triglyceride lipase CD68, cluster of differentiation 68 COX-2, cyclooxygenase-2 CPT1, carnitine palmitoyltransferase I CYP1A1, cytochrome P450 1A1 DHA, docosahexaenoic acid D6D, delta-6-desaturase ELOVL, fatty acid elongase EPA, eicosapentaenoic acid eWAT, epididymal white adipose tissue FAS, fatty acid synthase FFA, free fatty acid GAPDH, glyceraldehyde 3-phosphate dehydrogenase GPR120, G protein-coupled receptor 120 GPX1, glutathione peroxidase HF, high fat HSL, hormone sensitive lipase IL-6, interleukin-6 iWAT, inguinal white adipose tissue LCITMS, liquid chromatography ion-trap mass spectrometry LCPUFA, long-chain polyunsaturated fatty acid LTB, leukotriene B MAO, monoamine oxidase MEPG-1, macrophage expressed gene 1 NAFLD, non-alcohol fatty liver disease PFAOS, peroxisomal fatty acid oxidation system PGE, prostaglandin E PPAR, peroxisome proliferator-activated receptors ROS, reactive oxygen species SCD1, stearoyl-coenzyme A desaturase-1 SREBP, sterol regulatory element binding protein TBARS, thiobarbituric acid reactive substances TBP, TATAA-box binding protein TG, triglyceride TNF-α, tumor necrosis factor-α UCP, uncoupling protein VEGFR, vascular endothelial growth factor receptor |
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