Hepatic n-3 polyunsaturated fatty acid depletion promotes steatosis and insulin resistance in mice: genomic analysis of cellular targets.

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

doi:10.1371/journal.pone.0023365

Barbara D Pachikian, Patrice D Cani + Show 16 more

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https://doi.org/10.1371/journal.pone.0023365

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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.

Highlights

Dietary n-3 polyunsaturated fatty acid (PUFA) have important metabolic effects due to their involvement in eicosanoid biosynthesis and their ability to modulate the transcription of regulatory genes [1,2]
In accordance with the changes in arachidonic and oleic acid, we found a higher level of bioactive lipids belonging to the endocannabinoid system and known to control lipogenesis, namely 2-arachidonoylglycerol (2-AG) and N-oleoylethanolamine, in the liver of DEF mice than in control diet (CT) mice
Several papers suggest that decreased n-3/n-6 PUFA ratio in the diet is associated with changes in n-3/n-6 PUFA ratio in hepatic membrane phospholipids, on the one hand, and on the development of hepatic steatosis in humans, on the other hand [14,15,16]

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Introduction

Dietary n-3 polyunsaturated fatty acid (PUFA) have important metabolic effects due to their involvement in eicosanoid biosynthesis and their ability to modulate the transcription of regulatory genes [1,2]. N-3 PUFA promote fatty acid oxidation by binding and activating peroxisome proliferatoractivated receptor a (PPARa) [3,4]. Patients with hepatic steatosis present a lower n-3/n-6 PUFA ratio in liver tissue biopsies, namely in phospholipids subfractions, and in red blood cells [15,16]. In accordance with this observation, rats and mice presenting a depletion of n-3 PUFA for two generations display several features of metabolic syndrome including hepatic steatosis [17,18]

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