title: Resveratrol compounds inhibit human holocarboxylase synthetase and cause a lean phenotype in Drosophila melanogaster.
abstract: Holocarboxylase synthetase (HLCS) is the sole protein-biotin ligase in the human proteome. HLCS has key regulatory functions in intermediary metabolism, including fatty acid metabolism, and in gene repression through epigenetic mechanisms. The objective of this study was to identify food-borne inhibitors of HLCS that alter HLCS-dependent pathways in metabolism and gene regulation. When libraries of extracts from natural products and chemically pure compounds were screened for HLCS inhibitor activity, resveratrol compounds in grape materials caused an HLCS inhibition of >98% in vitro. The potency of these compounds was piceatannol>resveratrol>piceid. Grape-borne compounds other than resveratrol metabolites also contributed toward HLCS inhibition, e.g., p-coumaric acid and cyanidin chloride. HLCS inhibitors had meaningful effects on body fat mass. When Drosophila melanogaster brummer mutants, which are genetically predisposed to storing excess amounts of lipids, were fed diets enriched with grape leaf extracts and piceid, body fat mass decreased by more than 30% in males and females. However, Drosophila responded to inhibitor treatment with an increase in the expression of HLCS, which elicited an increase in the abundance of biotinylated carboxylases in vivo. We conclude that mechanisms other than inhibition of HLCS cause body fat loss in flies. We propose that the primary candidate is the inhibition of the insulin receptor/Akt signaling pathway.
authors: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, 316 Ruth Leverton Hall, Lincoln, NE 68583-0806, USA.
authors: Elizabeth L
authors: EL
authors: Cordonier
authors: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, 316 Ruth Leverton Hall, Lincoln, NE 68583-0806, USA.
authors: Riem
authors: R
authors: Adjam
authors: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, 316 Ruth Leverton Hall, Lincoln, NE 68583-0806, USA.
authors: Daniel Camara
authors: DC
authors: Teixeira
authors: Abteilung Molekulare Prävention, Institut für Humanernährung und Lebensmittelkunde, Universität Kiel, Heinrich-Hecht-Platz 10, 24118 Kiel, Germany.
authors: Simone
authors: S
authors: Onur
authors: Department of Food Science and Technology, University of Nebraska-Lincoln, 326 Filley Hall, Lincoln, NE 68583-0806, USA.
authors: Richard
authors: R
authors: Zbasnik
authors: Department of Agronomy, University of Nebraska-Lincoln, 377 Plant Science Hall, Lincoln, NE 68583-0724, USA.
authors: Paul E
authors: PE
authors: Read
authors: Abteilung Molekulare Prävention, Institut für Humanernährung und Lebensmittelkunde, Universität Kiel, Heinrich-Hecht-Platz 10, 24118 Kiel, Germany.
authors: Frank
authors: F
authors: Döring
authors: Department of Food Science and Technology, University of Nebraska-Lincoln, 326 Filley Hall, Lincoln, NE 68583-0806, USA.
authors: Vicki L
authors: VL
authors: Schlegel
authors: Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, 316 Ruth Leverton Hall, Lincoln, NE 68583-0806, USA. Electronic address: jzempleni2@unl.edu.
authors: Janos
authors: J
authors: Zempleni
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects*; D000818:Animals; D019921:Biotinylation / Q000187:drug effects; D019731:Carbon-Nitrogen Ligases / Q000037:antagonists & inhibitors*; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster / Q000187:drug effects* / Q000235:genetics; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008049:Lipase / Q000235:genetics; D008297:Male; D010936:Plant Extracts / Q000494:pharmacology; D000077185:Resveratrol; D013267:Stilbenes / Q000378:metabolism / Q000494:pharmacology*; D027843:Vitis / Q000737:chemistry
chemical_list: D029721:Drosophila Proteins; D004791:Enzyme Inhibitors; D010936:Plant Extracts; D013267:Stilbenes; D008049:Lipase; C559670:BMM protein, Drosophila; D019731:Carbon-Nitrogen Ligases; C023312:holocarboxylase synthetases; D000077185:Resveratrol
keywords: Drosophila; Fat mass; Grapes; Holocarboxylase synthetase; Inhibitor; Resveratrol compounds