title: Dietary procyanidins selectively modulate intestinal farnesoid X receptor-regulated gene expression to alter enterohepatic bile acid recirculation: elucidation of a novel mechanism to reduce triglyceridemia.
abstract: METHODS
  Understanding the molecular basis by which dietary procyanidins modulate triglyceride and cholesterol homeostasis has important implications for the use of natural products in the treatment and prevention of cardiovascular disease.
  
  
  METHODS
  To determine whether modulation of bile acid (BA) homeostasis contributes to the hypotriglyceridemic action of grape seed procyanidin extract (GSPE) we examined the effect on genes regulating BA absorption, transport and synthesis in vitro, in Caco-2 cells, and in vivo, in wild type (C57BL/6) and farnesoid x receptor knockout (Fxr(-/-)) mice.
  
  
  RESULTS
  We provide novel evidence demonstrating that GSPE is a naturally occurring gene-selective bile acid receptor modulator (BARM). Mechanistically, GSPE down-regulates genes involved in intestinal BA absorption and transport in an Fxr-dependent manner, resulting in decreased enterohepatic BA recirculation. This correlates with increased fecal BA output, decreased serum triglyceride and cholesterol levels, increased hepatic cholesterol 7α-hydroxylase (Cyp7a1), and decreased intestinal fibroblast growth factor 15 (Fgf15) expression. GSPE also increased hepatic HmgCoA reductase (Hmgcr) and synthase (Hmgcs1) expression, while concomitantly decreasing sterol regulatory element-binding protein 1c (Srebp1c).
  
  
  CONCLUSIONS
  GSPE selectively regulates intestinal Fxr-target gene expression in vivo, and modulation of BA absorption and transport is a critical regulatory point for the consequential hypotriglyceridemic effects of GSPE.
authors.affiliation: Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada Reno, Reno, Nevada, 89557.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Heidker
authors.affiliation: Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada Reno, Reno, Nevada, 89557.
authors.forename: Gianella C
authors.initials: GC
authors.lastname: Caiozzi
authors.affiliation: Department of Agriculture, Nutrition and Veterinary Sciences, University of Nevada Reno, Reno, Nevada, 89557.
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Ricketts
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D018938:Caco-2 Cells / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D005786:Gene Expression Regulation / Q000187:drug effects; D056604:Grape Seed Extract / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D044945:Proanthocyanidins / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002784:Cholesterol; D056604:Grape Seed Extract; D044945:Proanthocyanidins; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated
keywords: Bile acids; Enterohepatic recirculation; Fxr; Procyanidins; Triglycerides