title: The human fatty acid synthase gene and de novo lipogenesis are coordinately regulated in human adipose tissue.
abstract: Despite its potential importance in obesity and related disorders, little is known about regulation of lipogenesis in human adipose tissue. To investigate this area at the molecular and mechanistic levels, we studied lipogenesis and the regulation of 1 of its core enzymes, fatty acid synthase (FAS), in human adipose tissue in response to hormonal and nutritional manipulation. As a paradigm for lipogenic genes, we cloned the upstream region of the human FAS gene, compared its sequence to that of FAS orthologs from other species, and identified important regulatory elements that lie upstream of the FAS coding region. Lipogenesis, as assessed by glucose incorporation into lipids, was increased by insulin and more so by the combination of insulin and dexamethasone (Dex, a potent glucocorticoid analogue). In parallel, FAS expression, activity, and gene transcription rate were also significantly increased by these treatments. We also showed that linoleic acid, a representative PUFA, attenuated the actions of insulin and Dex on fatty acid and lipid synthesis as well as FAS activity and expression. Using reporter assays, we determined that the regions responsible for hormonal regulation of the FAS gene lie in the proximal portion of the gene's 5'-flanking region, within which we identified an insulin response element similar to the E-box sequence we identified previously in the rat FAS gene. In summary, we demonstrated that lipogenesis occurs in human adipose tissue and can be induced by insulin, further enhanced by glucocorticoids, and suppressed by PUFA in a hormone-dependent manner.
authors.affiliation: Department of Nutrition and Agricultural Experiment Station, University of Tennessee, Knoxville, TN 37996-1920,USA.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Wang
authors.forename: Brynn
authors.initials: B
authors.lastname: Jones Voy
authors.forename: Sumithra
authors.initials: S
authors.lastname: Urs
authors.forename: Suyeon
authors.initials: S
authors.lastname: Kim
authors.forename: Morvarid
authors.initials: M
authors.lastname: Soltani-Bejnood
authors.forename: Neil
authors.initials: N
authors.lastname: Quigley
authors.forename: Young-Ran
authors.initials: YR
authors.lastname: Heo
authors.forename: Melissa
authors.initials: M
authors.lastname: Standridge
authors.forename: Brett
authors.initials: B
authors.lastname: Andersen
authors.forename: Madhu
authors.initials: M
authors.lastname: Dhar
authors.forename: Rashika
authors.initials: R
authors.lastname: Joshi
authors.forename: Patrick
authors.initials: P
authors.lastname: Wortman
authors.forename: James W
authors.initials: JW
authors.lastname: Taylor
authors.forename: Joseph
authors.initials: J
authors.lastname: Chun
authors.forename: Michael
authors.initials: M
authors.lastname: Leuze
authors.forename: Kate
authors.initials: K
authors.lastname: Claycombe
authors.forename: Arnold M
authors.initials: AM
authors.lastname: Saxton
authors.forename: Naima
authors.initials: N
authors.lastname: Moustaid-Moussa
mesh_terms: D000273:Adipose Tissue / Q000201:enzymology / Q000378:metabolism*; D000328:Adult; D001483:Base Sequence; D046508:Culture Techniques; D003907:Dexamethasone / Q000494:pharmacology; D064429:Fatty Acid Synthases / Q000235:genetics*; D005227:Fatty Acids / Q000096:biosynthesis; D005260:Female; D015870:Gene Expression; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008055:Lipids / Q000096:biosynthesis*; D008875:Middle Aged; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000502:physiology
chemical_list: D005227:Fatty Acids; D005938:Glucocorticoids; D007328:Insulin; D008055:Lipids; D003907:Dexamethasone; D064429:Fatty Acid Synthases; D005947:Glucose