title: Docosahexaenoic acid suppresses the expression of FoxO and its target genes.
abstract: Docosahexaenoic acid (DHA), an n-3 polyunsaturated fatty acid, has previously been shown to ameliorate obesity-associated metabolic syndrome. To decipher the mechanism responsible for the beneficial effects of DHA on energy/glucose homeostasis and the metabolic syndrome, 30 weaned cross-bred pigs were randomly assigned to three groups and fed ad libitum with a standard diet supplemented with 2% of beef tallow, soybean oil or DHA oil for 30 days, and the gene expression profile of various tissues was evaluated by quantitative real-time polymerase chain reaction. The DHA-supplemented diets reduced the expression of forkhead box O transcription factor (FoxO) 1 and FoxO3 in the liver and adipose tissue. DHA treatments also decreased the expression of FoxO1 and FoxO3 in human hepatoma cells, SK-HEP-1 and human and porcine primary adipocytes. In addition, DHA also down-regulated FoxO target genes, such as microsomal triacylglycerol transfer protein (MTP), glucose-6-phosphatase, apolipoprotein C-III (apoC-III) and insulin-like growth factor binding-protein 1 in the liver, as well as reduced total plasma levels of cholesterol and triacylglycerol in the pig. Transcriptional suppression of FoxO1, FoxO3, apoC-III and MTP by DHA was further confirmed by reporter assays with each promoter construct. Taken together, our study indicates that DHA modulates lipid and glucose homeostasis in part by down-regulating FoxO function. The down-regulation of genes associated with triacylglycerol metabolism and very low density lipoprotein assembly is likely to contribute to the beneficial effects of DHA on the metabolic syndrome.
authors.affiliation: Center for Biotechnology / Department of Animal Science and Technology, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Chen
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Chen
authors.forename: Tsai-Kun
authors.initials: TK
authors.lastname: Li
authors.forename: Pei-Hwa
authors.initials: PH
authors.lastname: Wang
authors.forename: Li-Ru
authors.initials: LR
authors.lastname: Liu
authors.forename: Fang-Ying
authors.initials: FY
authors.lastname: Chang
authors.forename: Ya-Chin
authors.initials: YC
authors.lastname: Wang
authors.forename: Yu-Hsiang
authors.initials: YH
authors.lastname: Yu
authors.forename: Shau-Ping
authors.initials: SP
authors.lastname: Lin
authors.forename: Harry J
authors.initials: HJ
authors.lastname: Mersmann
authors.forename: Shih-Torng
authors.initials: ST
authors.lastname: Ding
mesh_terms: D017667:Adipocytes / Q000187:drug effects; D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D002784:Cholesterol / Q000097:blood; D019587:Dietary Supplements; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D005260:Female; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D005947:Glucose / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics; D008297:Male; D060888:Real-Time Polymerase Chain Reaction; D013552:Swine / Q000235:genetics; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
chemical_list: C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D014280:Triglycerides; D004281:Docosahexaenoic Acids; D002784:Cholesterol; D005947:Glucose