Dietary procyanidins enhance transcriptional activity of bile acid-activated FXR in vitro and reduce triglyceridemia in vivo in a FXR-dependent manner.
Consumption of dietary flavonoids has been associated with reduced mortality and risk of cardiovascular disease, partially by reducing triglyceridemia. We have previously reported that a grape seed procyanidin extract (GSPE) reduces postprandial triglyceridemia in normolipidemic animals signaling through the orphan nuclear receptor small heterodimer partner (SHP) a target of the bile acid receptor farnesoid X receptor (FXR). Our aim was to elucidate whether FXR mediates the hypotriglyceridemic effect of procyanidins. In FXR-driven luciferase expression assays GSPE dose-dependently enhanced FXR activity in the presence of chenodeoxycholic acid. GSPE gavage reduced triglyceridemia in wild type mice but not in FXR-null mice, revealing FXR as an essential mediator of the hypotriglyceridemic actions of procyanidins in vivo. In the liver, GSPE downregulated, in an FXR-dependent manner, the expression of the transcription factor steroid response element binding protein 1 (SREBP1) and several SREBP1 target genes involved in lipogenesis, and upregulated ApoA5 expression. Altogether, our results indicate that procyanidins lower triglyceridemia following the same pathway as bile acids: activation of FXR, transient upregulation of SHP expression and subsequent downregulation of SREBP1 expression. This study adds dietary procyanidins to the arsenal of FXR ligands with potential therapeutic use to combat hypertriglyceridemia, type 2 diabetes and metabolic syndrome.
Del Bas
Josep Maria
JM
Departament de Bioquímica i Biotecnología, Universitat Rovira i Virgili, Campus Sescelades, Tarragona, Spain.
Ricketts
Marie-Louise
ML
Vaqué
Montserrat
M
Sala
Esther
E
Quesada
Helena
H
Ardevol
Anna
A
Salvadó
M Josepa
MJ
Blay
Mayte
M
Arola
Lluís
L
Moore
David D
DD
Pujadas
Gerard
G
Fernandez-Larrea
Juan
J
Bladé
Cinta
C
D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D056604:Grape Seed Extract; D006801:Humans; D015228:Hypertriglyceridemia / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D010936:Plant Extracts / Q000494:pharmacology*; D044945:Proanthocyanidins / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D056604:Grape Seed Extract; D010936:Plant Extracts; D044945:Proanthocyanidins; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D000099150:Receptor, Farnesoid X-Activated; C511402:Grape Seed Proanthocyanidins