title: Increasing intake of long-chain n-3 PUFA enhances lipoperoxidation and modulates hepatic gene expression in a dose-dependent manner.
abstract: Long-chain (LC) n-3 PUFA have a broad range of biological properties that can be achieved at the gene expression level. This has been well described in liver, where LC n-3 PUFA modulate the expression of genes related to lipid metabolism. However, the complexity of biological pathway modulations and the nature of bioactive molecules are still under investigation. The present study aimed to investigate the dose-response effects of LC n-3 PUFA on the production of peroxidised metabolites, as potential bioactive molecules, and on global gene expression in liver. Hypercholesterolaemic rabbits received by daily oral administration (7 weeks) either oleic acid-rich oil or a mixture of oils providing 0.1, 0.5 or 1 % (groups 1, 2 and 3 respectively) of energy as DHA. Levels of specific peroxidised metabolites, namely 4-hydroxyhexenal (4-HHE)-protein adducts, issued from LC n-3 PUFA were measured by GC/MS/MS in liver in parallel to transcription profiling. The intake of LC n-3 PUFA increased, in a dose-dependent manner, the hepatic production of 4-HHE. At the highest dose, LC n-3 PUFA provoked an accumulation of TAG in liver, which can be directly linked to increased mRNA levels of lipoprotein hepatic receptors (LDL-receptor and VLDL-receptor). In groups 1 and 2, the mRNA levels of microsomal TAG transfer protein decreased, suggesting a possible new mechanism to reduce VLDL secretion. These modulations of genes related to lipoprotein metabolism were independent of PPARα signalling but were probably linked to the activation of the farnesol X receptor pathway by LC n-3 PUFA and/or their metabolites such as HHE.
authors.affiliation: INRA, UMR 1019, UNH, CRNH Auvergne, Clermont-Ferrand, F-63122 St Genès Champanelle, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Gladine
authors.affiliation: Food Nutrition Genomics Team, Agri-Foods and Health Section, AgResearch Grasslands, Palmerston North 4442, New Zealand.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Roy
authors.affiliation: INRA, UMR 1019, UNH, CRNH Auvergne, Clermont-Ferrand, F-63122 St Genès Champanelle, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Rigaudière
authors.affiliation: INRA, UMR 1019, UNH, CRNH Auvergne, Clermont-Ferrand, F-63122 St Genès Champanelle, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Laillet
authors.affiliation: INRA, UMR 1019, UNH, CRNH Auvergne, Clermont-Ferrand, F-63122 St Genès Champanelle, France.
authors.forename: Georges
authors.initials: G
authors.lastname: Da Silva
authors.affiliation: INRA, UMR 1019, UNH, CRNH Auvergne, Clermont-Ferrand, F-63122 St Genès Champanelle, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Joly
authors.affiliation: INRA, UMR 1019, UNH, CRNH Auvergne, Clermont-Ferrand, F-63122 St Genès Champanelle, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Pujos-Guillot
authors.affiliation: INRA, UMR 1019, UNH, CRNH Auvergne, Clermont-Ferrand, F-63122 St Genès Champanelle, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Morio
authors.affiliation: INRA, UMR 866, Dynamique Musculaire et Métabolisme, Montpellier, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Feillet-Coudray
authors.affiliation: Food Nutrition Genomics Team, Agri-Foods and Health Section, AgResearch Grasslands, Palmerston North 4442, New Zealand.
authors.forename: Warren C
authors.initials: WC
authors.lastname: McNabb
authors.affiliation: INRA, UMR 1019, UNH, CRNH Auvergne, Clermont-Ferrand, F-63122 St Genès Champanelle, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Chardigny
authors.affiliation: INRA, UMR 1019, UNH, CRNH Auvergne, Clermont-Ferrand, F-63122 St Genès Champanelle, France.
authors.forename: Blandine
authors.initials: B
authors.lastname: Comte
mesh_terms: D000284:Administration, Oral; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D004305:Dose-Response Relationship, Drug; D015525:Fatty Acids, Omega-3 / Q000378:metabolism*; D008401:Gas Chromatography-Mass Spectrometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006937:Hypercholesterolemia / Q000188:drug therapy; D050356:Lipid Metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism*; D008862:Microsomes, Liver / Q000378:metabolism; D011817:Rabbits; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000447:Aldehydes; D015525:Fatty Acids, Omega-3; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C063409:4-hydroxyhexenal