Resveratrol compounds inhibit human holocarboxylase synthetase and cause a lean phenotype in Drosophila melanogaster

Elizabeth L. Cordonier, Riem Adjam, Daniel Camara Teixeira, Simone Onur, Richard Zbasnik, Paul E. Read, Frank Döring, Vicki L Schlegel, Janos Zempleni

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1379-1384
Number of pages6
JournalJournal of Nutritional Biochemistry
Volume26
Issue number11
DOIs
StatePublished - Nov 2015

Fingerprint

Drosophila melanogaster
Phenotype
Vitis
Metabolism
Adipose Tissue
Fats
Epigenetic Repression
resveratrol
holocarboxylase synthetases
Insulin Receptor
Proteome
Ligases
Nutrition
Biotin
Metabolites
Biological Products
Gene expression
Diptera
Genes
Libraries

Keywords

  • Drosophila
  • Fat mass
  • Grapes
  • Holocarboxylase synthetase
  • Inhibitor
  • Resveratrol compounds

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Biology
  • Nutrition and Dietetics
  • Clinical Biochemistry

Cite this

Resveratrol compounds inhibit human holocarboxylase synthetase and cause a lean phenotype in Drosophila melanogaster. / Cordonier, Elizabeth L.; Adjam, Riem; Teixeira, Daniel Camara; Onur, Simone; Zbasnik, Richard; Read, Paul E.; Döring, Frank; Schlegel, Vicki L; Zempleni, Janos.

In: Journal of Nutritional Biochemistry, Vol. 26, No. 11, 11.2015, p. 1379-1384.

Research output: Contribution to journalArticle

Cordonier, Elizabeth L. ; Adjam, Riem ; Teixeira, Daniel Camara ; Onur, Simone ; Zbasnik, Richard ; Read, Paul E. ; Döring, Frank ; Schlegel, Vicki L ; Zempleni, Janos. / Resveratrol compounds inhibit human holocarboxylase synthetase and cause a lean phenotype in Drosophila melanogaster. In: Journal of Nutritional Biochemistry. 2015 ; Vol. 26, No. 11. pp. 1379-1384.
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AB - 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.

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