Dietary procyanidins lower triglyceride levels signaling through the nuclear receptor small heterodimer partner.
Hypertriglyceridemia is an independent risk factor in the development of cardiovascular diseases, and we have previously reported that oral administration of a grape seed procyanidin extract (GSPE) drastically decreases plasma levels of triglycerides (TG) and apolipoprotein B (ApoB) in normolipidemic rats, with a concomitant induction in the hepatic expression of the nuclear receptor small heterodimer partner (NR0B2/SHP). Our objective in this study was to elucidate whether SHP is the mediator of the reduction of TG-rich ApoB-containing lipoproteins triggered by GSPE. We show that GSPE inhibited TG and ApoB secretion in human hepatocarcinoma HepG2 cells and had and hypotriglyceridemic effect in wild-type mouse. The TG-lowering action of GSPE was abolished in HepG2 cells transfected with a SHP-specific siRNA and in a SHP-null mouse. Moreover, in mouse liver, GSPE downregulated several lipogenic genes, including steroid response element binding protein 1c (SREBP-1c), and upregulated carnitine palmitoyltransferase-1A (CPT-1A) and apolipoprotein A5 (ApoA5), in a SHP-dependent manner. In HepG2 cells GSPE also inhibited ApoB secretion, but in a SHP-independent manner. In conclusion, SHP is a key mediator of the hypotriglyceridemic response triggered by GSPE. This novel signaling pathway of procyanidins through SHP may be relevant to explain the health effects ascribed to the regular consumption of dietary flavonoids.
Del Bas
Josep Maria
JM
Departament de Bioquímica i Biotecnología, Universitat Rovira i Virgili, Campus Sescelades, Tarragona, Spain.
Ricketts
Marie Louise
ML
Baiges
Isabel
I
Quesada
Helena
H
Ardevol
Anna
A
Salvadó
Maria Josepa
MJ
Pujadas
Gerard
G
Blay
Mayte
M
Arola
Lluis
L
Bladé
Cinta
C
Moore
David D
DD
Fernandez-Larrea
Juan
J
D000818:Animals; D001055:Apolipoproteins B / Q000096:biosynthesis* / Q000187:drug effects; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D020868:Gene Silencing; D006801:Humans; D015228:Hypertriglyceridemia / Q000188:drug therapy / Q000517:prevention & control; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010936:Plant Extracts / Q000494:pharmacology*; D044945:Proanthocyanidins / Q000378:metabolism / Q000494:pharmacology*; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D012639:Seeds / Q000737:chemistry; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000096:biosynthesis*; D027843:Vitis / Q000737:chemistry
D001055:Apolipoproteins B; D010936:Plant Extracts; D044945:Proanthocyanidins; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; C099713:nuclear receptor subfamily 0, group B, member 2; D002334:Carnitine O-Palmitoyltransferase