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. 2015 Nov;26(11):1379-84.
doi: 10.1016/j.jnutbio.2015.07.004. Epub 2015 Jul 26.

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

Elizabeth L Cordonier  1 , Riem Adjam  1 , Daniel Camara Teixeira  1 , Simone Onur  2 , Richard Zbasnik  3 , Paul E Read  4 , Frank Döring  2 , Vicki L Schlegel  3 , Janos Zempleni  5
Affiliations

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

Elizabeth L Cordonier et al. J Nutr Biochem. 2015 Nov.

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.

Keywords: Drosophila; Fat mass; Grapes; Holocarboxylase synthetase; Inhibitor; Resveratrol compounds.

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Figures

Fig. 1
Fig. 1
Representative example of HLCS activity in samples treated with extracts from the PECKISH library of natural compounds. HLCS activity was assayed using a 96-well plate format, values in individual wells denote HLCS activity (% of controls). Identifiers: B3 and B4 = vehicle controls; C3 = grape leaf extract; A4 = Cassia fistula; C7 = Syzygium cumini; row H is the calibration curve containing defined amounts of HLCS.
Fig. 2
Fig. 2
(A) Gel-based assay of HLCS activity in the absence and presence of grape leaf extract. A sample without HLCS was used as negative control. Extracts from maté leaves and oranges were not considered for subsequent studies, because of their inhibitor activity was caused by shifts in the assay pH as discussed in the text. (B) Comparison of leaf extracts from Gruner Veltliner, St. Croix, and Edelweiss. HLCS activity was measured in the presence of and aqueous extract of 500 µg grape leaves in a sample volume of 50 µL; controls were prepared using vehicle and by omitting HLCS. Lanes were electronically re-arranged to facilitate comparisons. (C) Effects of grape juices on HLCS activity. (D) Effects of crushed white grapes on HLCS activity, quantified by gel densitometry. (E) Effects of pomace extract (variety Edelweiss) on HLCS activity.
Fig. 3
Fig. 3
Comparison of the effects of resveratrol, piceatannol, and piceid on the inhibition of HLCS.
Fig. 4
Fig. 4
Effect of grape leaf extract on body fat mass in male and female Drosophila melanogaster brummer mutants 15828 (panels A and B) and 15959 (panels C and D). Flies were fed a diet supplemented with 0.05 or 1% grape leaf solids (as extracts) for 21 days; controls were fed an extract-free diet. a,bBars not sharing the same letter are significantly different (P < 0.05; n=4 tubes, each containing 40 flies).
Fig. 5
Fig. 5
Effect of piceid (panels A and B) and soraphen A (panels C and D) on body fat mass in male and female Drosophila melanogaster brummer mutant 15828. Flies were fed a diet supplemented with 0.012 µmol/L piceid, 0.12 µmol/L piceid, or 5 µmol/L soraphen A for 21 days; controls were fed piceid-free and soraphen A-free diets. a,bBars not sharing the same letter are significantly different (P < 0.05; n=4 tubes, each containing 40 flies).
Fig. 6
Fig. 6
Abundance of biotinylated holocaboxylases and HLCS in in male and female Drosophila melanogaster brummer mutant 15828. Flies were fed a diet supplemented with 0.05 or 1% grape leaf solids (GLS, as extracts) for 21 days; controls were fed an extract-free diet. Biotinylated carboxylases, HLCS, and β-actin (control) were probed using streptavidin, anti-HLCS, and anti-β-actin, respectively. ACC, acetyl-CoA carboxylases; MCC, 3-methylcrotonyl-CoA carboxylase; PC, pyruvate carboxylase; PCC, propionyl-CoA carboxylase.
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