Journal Article

Hepatic n-3 Polyunsaturated Fatty Acid Depletion Promotes Steatosis and Insulin Resistance in Mice: Genomic Analysis of Cellular Targets

Delzenne, Nathalie M., Pachikian, Barbara D., Neyrinck, Audrey M., Molendi-Coste, Olivier, Francaux, Marc, Catry, Emilie, Carpentier, Yvon A., Cani, Patrice D., Leclercq, Isabelle A., Muccioli, Giulio G., Demoulin, Jean-Baptiste, Dejeans, Nicolas, Dewulf, Evelyne M., Foufelle, Fabienne, De Backer, Fabienne C., Deldicque, Louise, Portois, Laurence, Sohet, Florence M., Essaghir, Ahmed

2011

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation / Animals / Biology / Cannabinoid Receptor Modulators - metabolism / Cholesterol - biosynthesis / Depletion / Diet / Endoplasmic reticulum / Endoplasmic Reticulum Stress - genetics / Enzymes / Fatty acids / Fatty Acids, Omega-3 - metabolism / Fatty liver / Fatty Liver - genetics / Fatty Liver - pathology / Feeding Behavior / Gene Expression Regulation / Genetic research / Genome - genetics / Genomic analysis / Insulin / Insulin resistance / Insulin Resistance - genetics / Lipid Metabolism - genetics / Lipids / Lipogenesis / Liver / Liver - metabolism / Liver - pathology / Liver diseases / Liver X Receptors / Medicine / Mice / Nutrition research / Oligonucleotide Array Sequence Analysis / Orphan Nuclear Receptors - metabolism / Oxidation / Oxidation-Reduction / Phospholipids / Phospholipids - metabolism / Polyunsaturated fatty acids / Protein binding / Reproducibility of Results / RNA, Messenger - genetics / RNA, Messenger - metabolism / Rodents / Secretion / Steatosis / Sterol Regulatory Element Binding Protein 1 - metabolism / Sterol regulatory element-binding protein / Triglycerides - metabolism