title: An integrative metabolism approach identifies stearoyl-CoA desaturase as a target for an arachidonate-enriched diet.
abstract: Epidemiological studies have correlated diets containing higher intakes of PUFA with lower rates of chronic metabolic diseases. The molecular mechanisms regulated by the consumption of PUFA were examined by using an integrative metabolism approach assaying the liver transcriptome and lipid-metabolome of mice fed a control diet, an arachidonate (AA)-enriched fungal oil, an eicosapentaenoic (EPA)/docosahexaenoic (DHA)-enriched fish oil, or a combination of the two oils. Hepatic gene transcription and fatty acid (FA) metabolism were significantly altered by diets enriched with AA, as revealed by global error assessment and singular value decomposition (SVD) analysis, respectively. SVD analysis of the lipid data, reinforced with transcriptomics, suggests that the chronic feeding of AA modulates molecular endpoints similar to those previously reported in the obesity-resistant SCD1-/- mouse, namely, genes involved in lipid oxidation/synthesis and the significant changes in FA metabolism stemming from a repressed SCD1 activity. Specifically, the total levels and FA composition of several phospholipid (PL) species were significantly changed, with phosphatidylcholine (PC) demonstrating the greatest alterations. Reduced PC levels were linked to decreased expression of enzymes in PC biosynthesis (choline kinase, -2.2-fold; glycerol-3-phosphate acyltransferase, -2.0-fold). Alterations in PL-FA composition were related to decreased expression of FA biosynthetic genes [fatty acid synthetase, -3.7-fold; stearoyl-CoA desaturase-1 (SCD1), -1.8-fold]. Lower hepatic SCD1 gene expression levels were reflected in various aspects of FA metabolism through increased concentrations of palmitic (fungal oil, +45%; combination, +106%) and stearic acids (fungal oil, +60%; combination, +63%) in PC. Importantly, an integrated approach showed that these effects were not attenuated by the addition of an EPA/DHA-enriched fish oil, thereby identifying a previously unrecognized and distinct role for AA in the regulation of hepatic lipid metabolism.
authors.affiliation: Nestlé Research Center, Vers-chez-les-Blanc, Lausanne, Switzerland.
authors.forename: David M
authors.initials: DM
authors.lastname: Mutch
authors.forename: Martin
authors.initials: M
authors.lastname: Grigorov
authors.forename: Alvin
authors.initials: A
authors.lastname: Berger
authors.forename: Laurent B
authors.initials: LB
authors.lastname: Fay
authors.forename: Matthew-Alan
authors.initials: MA
authors.lastname: Roberts
authors.forename: Steven M
authors.initials: SM
authors.lastname: Watkins
authors.forename: Gary
authors.initials: G
authors.lastname: Williamson
authors.forename: J Bruce
authors.initials: JB
authors.lastname: German
mesh_terms: D000818:Animals; D016718:Arachidonic Acid / Q000008:administration & dosage* / Q000378:metabolism; D002797:Choline Kinase / Q000378:metabolism; D004032:Diet; D004042:Dietary Fats, Unsaturated / Q000008:administration & dosage*; D004281:Docosahexaenoic Acids / Q000378:metabolism; D005395:Fish Oils / Q000008:administration & dosage; D005658:Fungi; D015870:Gene Expression; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000378:metabolism; D006624:Hippocampus / Q000737:chemistry; D008099:Liver / Q000737:chemistry / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D010713:Phosphatidylcholines / Q000032:analysis; D010714:Phosphatidylethanolamines / Q000032:analysis; D010716:Phosphatidylinositols / Q000032:analysis; D010718:Phosphatidylserines / Q000032:analysis; D010743:Phospholipids / Q000032:analysis / Q000378:metabolism; D013230:Stearoyl-CoA Desaturase / Q000235:genetics / Q000378:metabolism*
chemical_list: D004042:Dietary Fats, Unsaturated; D005395:Fish Oils; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010716:Phosphatidylinositols; D010718:Phosphatidylserines; D010743:Phospholipids; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D013230:Stearoyl-CoA Desaturase; D005992:Glycerol-3-Phosphate O-Acyltransferase; D002797:Choline Kinase