The Human Fatty Acid Synthase Gene and De Novo Lipogenesis Are Coordinately Regulated in Human Adipose Tissue

Yanxin Wang, University of Tennessee - Knoxville
Brynn Jones Voy, Oak Ridge National Laboratory
Sumithra Urs, University of Tennessee - Knoxville
Suyeon Kim, University of Tennessee - Knoxville
Morvarid Soltani-Bejnood, University of Tennessee - Knoxville
Neil Quigley, University of Tennessee - Knoxville
Young-Ran Heo, University of Tennessee - Knoxville
Melissa Standridge, University of Tennessee - Knoxville
Brett Anderson, University of Tennessee - Knoxville
Madhu S. Dhar, University of Tennessee, Knoxville
Rashika Joshi, University of Tennessee - Knoxville
Patrick Wortman, University of Tennessee - Knoxville
James W. Taylor, University of Tennessee - Knoxville
Joseph Chun, University of Tennessee - Knoxville
Michael Leuze, Oak Ridge National Laboratory
Kate Claycombe, Michigan State University
Arnold M. Saxton, University of Tennessee - Knoxville
Naima Moustaid-Moussa, University of Tennessee - Knoxville

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.