title: Omega-3 phospholipids from fish suppress hepatic steatosis by integrated inhibition of biosynthetic pathways in dietary obese mice.
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. Antiinflammatory, hypolipidemic, and insulin-sensitizing effects ofDHA/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 7 weeks 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 (10 mg/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 cHlF-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 downregulation 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 downregulation 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.
authors.forename: Martin
authors.initials: M
authors.lastname: Rossmeisl
authors.forename: Dasa
authors.initials: D
authors.lastname: Medrikova
authors.forename: Evert M
authors.initials: EM
authors.lastname: van Schothorst
authors.forename: Jana
authors.initials: J
authors.lastname: Pavlisova
authors.forename: Ondrej
authors.initials: O
authors.lastname: Kuda
authors.forename: Michal
authors.initials: M
authors.lastname: Hensler
authors.forename: Kristina
authors.initials: K
authors.lastname: Bardova
authors.forename: Pavel
authors.initials: P
authors.lastname: Flachs
authors.forename: Barbora
authors.initials: B
authors.lastname: Stankova
authors.forename: Marek
authors.initials: M
authors.lastname: Vecka
authors.forename: Eva
authors.initials: E
authors.lastname: Tvrzicka
authors.forename: Ales
authors.initials: A
authors.lastname: Zak
authors.forename: Jaap
authors.initials: J
authors.lastname: Keijer
authors.forename: Jan
authors.initials: J
authors.lastname: Kopecky
mesh_terms: D000818:Animals; D053898:Biosynthetic Pathways / Q000187:drug effects; D002784:Cholesterol / Q000096:biosynthesis; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005234:Fatty Liver / Q000517:prevention & control*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease; D010743:Phospholipids / Q000494:pharmacology*; D014280:Triglycerides / Q000096:biosynthesis
chemical_list: D015525:Fatty Acids, Omega-3; D010743:Phospholipids; D014280:Triglycerides; D002784:Cholesterol