title: Hepatic n-3 polyunsaturated fatty acid depletion promotes steatosis and insulin resistance in mice: genomic analysis of cellular targets.
abstract: Patients with non-alcoholic fatty liver disease are characterised by a decreased n-3/n-6 polyunsaturated fatty acid (PUFA) ratio in hepatic phospholipids. The metabolic consequences of n-3 PUFA depletion in the liver are poorly understood. We have reproduced a drastic drop in n-3 PUFA among hepatic phospholipids by feeding C57Bl/6J mice for 3 months with an n-3 PUFA depleted diet (DEF) versus a control diet (CT), which only differed in the PUFA content. DEF mice exhibited hepatic insulin resistance (assessed by euglycemic-hyperinsulinemic clamp) and steatosis that was associated with a decrease in fatty acid oxidation and occurred despite a higher capacity for triglyceride secretion. Microarray and qPCR analysis of the liver tissue revealed higher expression of all the enzymes involved in lipogenesis in DEF mice compared to CT mice, as well as increased expression and activation of sterol regulatory element binding protein-1c (SREBP-1c). Our data suggest that the activation of the liver X receptor pathway is involved in the overexpression of SREBP-1c, and this phenomenon cannot be attributed to insulin or to endoplasmic reticulum stress responses. In conclusion, n-3 PUFA depletion in liver phospholipids leads to activation of SREBP-1c and lipogenesis, which contributes to hepatic steatosis.
authors.affiliation: Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Barbara D
authors.initials: BD
authors.lastname: Pachikian
authors.forename: Ahmed
authors.initials: A
authors.lastname: Essaghir
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Demoulin
authors.forename: Audrey M
authors.initials: AM
authors.lastname: Neyrinck
authors.forename: Emilie
authors.initials: E
authors.lastname: Catry
authors.forename: Fabienne C
authors.initials: FC
authors.lastname: De Backer
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dejeans
authors.forename: Evelyne M
authors.initials: EM
authors.lastname: Dewulf
authors.forename: Florence M
authors.initials: FM
authors.lastname: Sohet
authors.forename: Laurence
authors.initials: L
authors.lastname: Portois
authors.forename: Louise
authors.initials: L
authors.lastname: Deldicque
authors.forename: Olivier
authors.initials: O
authors.lastname: Molendi-Coste
authors.forename: Isabelle A
authors.initials: IA
authors.lastname: Leclercq
authors.forename: Marc
authors.initials: M
authors.lastname: Francaux
authors.forename: Yvon A
authors.initials: YA
authors.lastname: Carpentier
authors.forename: Fabienne
authors.initials: F
authors.lastname: Foufelle
authors.forename: Giulio G
authors.initials: GG
authors.lastname: Muccioli
authors.forename: Patrice D
authors.initials: PD
authors.lastname: Cani
authors.forename: Nathalie M
authors.initials: NM
authors.lastname: Delzenne
mesh_terms: D000818:Animals; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis; D004032:Diet; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D005234:Fatty Liver / Q000235:genetics* / Q000473:pathology; D005247:Feeding Behavior; D005786:Gene Expression Regulation; D016678:Genome / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D000071518:Liver X Receptors; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: D063385:Cannabinoid Receptor Modulators; D015525:Fatty Acids, Omega-3; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010743:Phospholipids; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D002784:Cholesterol