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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
Author(s) -
Heidker Rebecca M.,
Caiozzi Gianella C.,
Ricketts MarieLouise
Publication year - 2016
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.201500795
Subject(s) - farnesoid x receptor , cholesterol 7 alpha hydroxylase , bile acid , pregnane x receptor , chemistry , enterohepatic circulation , small heterodimer partner , cholesterol , medicine , biochemistry , biology , endocrinology , nuclear receptor , transcription factor , gene
Scope 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 ). Conclusion 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.