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Rossmeisl M (1), Medrikova D (1), van Schothorst EM (2), Pavlisova J (1), Kuda O (1), Hensler M (1), Bardova K (1), Flachs P (1), Stankova B (3), Vecka M (3), Tvrzicka E (3), Zak A (3), Keijer J (2), Kopecky J (1)

Biochim Biophys Acta. 2014;1841(2):267-278

(1) Department of Adipose Tissue Biology, Institute of Physiology Academy of Sciences of the Czech Republic v.v.i., Prague, Czech Republic.

(2) Human and Animal Physiology, Wageningen University, Wageningen, Netherlands.

(3) 4th Department of Internal Medicine, 1st Faculty of Medicine of Charles University and the General Teaching Hospital, Prague, Czech Republic.

Abstract

Non-alcoholic fatty liver disease (NAFLD) accompanies obesity and insulin resistance. Recent meta-analysis suggested omega-3 polyunsaturated fatty acids DHA and EPA to decrease liver fat in NAFLD patients. Anti-inflammatory, hypolipidemic, and insulin-sensitizing effects of DHA/EPA depend on their lipid form, with marine phospholipids showing better efficacy than fish oils. We characterized the mechanisms underlying beneficial effects of DHA/EPA phospholipids, alone or combined with an antidiabetic drug, on hepatosteatosis. C57BL/6N mice were fed for 7weeks an obesogenic high-fat diet (cHF) or cHF-based interventions: (i) cHF supplemented with phosphatidylcholine-rich concentrate from herring (replacing 10% of dietary lipids; PC), (ii) cHF containing rosiglitazone (10mg/kg diet; R), or (iii) PC+R. Metabolic analyses, hepatic gene expression and lipidome profiling were performed. Results showed that PC and PC+R prevented cHF-induced weight gain and glucose intolerance, while all interventions reduced abdominal fat and plasma triacylglycerols. PC and PC+R also lowered hepatic and plasma cholesterol and reduced hepatosteatosis. Microarray analysis revealed integrated down-regulation of hepatic lipogenic and cholesterol biosynthesis pathways by PC, while R-induced lipogenesis was fully counteracted in PC+R. Gene expression changes in PC and PC+R were associated with preferential enrichment of hepatic phosphatidylcholine and phosphatidylethanolamine fractions by DHA/EPA. The complex down-regulation of hepatic lipogenic and cholesterol biosynthesis genes and the antisteatotic effects were unique to DHA/EPA-containing phospholipids, since they were absent in mice fed soy-derived phosphatidylcholine. Thus, inhibition of lipid and cholesterol biosynthesis associated with potent antisteatotic effects in the liver in response to DHA/EPA-containing phospholipids support their use in NAFLD prevention and treatment.

KEYWORDS: CLS, Chow, DHA, EPA, FA, FDR, GEO, GSEA, Gene Expression Omnibus, Gene Set Enrichment Analysis, HDL-C, HMW, HOMA, High-fat diet, LA, Lipogenesis, Marine phospholipids, NAFLD, NEFA, Obesity, PC, PC+R, PCA, PPAR, PUFA, R, SHP, TC, TG, TZD, VIP, VLDL-TG, WAT, cHF, cHF supplemented with an antidiabetic drug rosiglitazone, cHF supplemented with marine phospholipids, cHF supplemented with marine phospholipids and rosiglitazone, corn oil-based high-fat diet, crown-like structures, docosahexaenoic acid, eicosapentaenoic acid, false discovery rate, fatty acids, high molecular weight, high-density lipoprotein cholesterol, homeostasis model assessment, linoleic acid, long-chain n-3 polyunsaturated fatty acids of marine origin, non-alcoholic fatty liver disease, non-esterified fatty acids, oPLS-DA, omega-3, omega-3 PL, omega-3 TG, omega-3 as marine phospholipids, omega-3 as triacylglycerols in fish oil, orthogonal partial least squares-discriminant analysis, peroxisome proliferator-activated receptor, principal component analysis, qPCR, real-time quantitative RT-PCR, small heterodimer partner, standard low-fat diet, thiazolidinedione, total cholesterol, triacylglycerol, variable important to projection, very low-density lipoprotein triacylglycerol, white adipose tissue.

doi: 10.1016/j.bbalip.2013.11.010.

Event date: 01/12/2013

Publication date: 30/04/2014