Conditional Gata4 deletion in mice induces bile acid absorption in the proximal small intestine.
OBJECTIVE
The transcription factor GATA4 is expressed throughout most of the small intestine except distal ileum, and restricts expression of the apical sodium-dependent bile acid transporter (ASBT), the rate-limiting intestinal bile acid transporter, to distal ileum. The hypothesis was tested that reduction of GATA4 activity in mouse small intestine results in an induction of bile acid transport in proximal small intestine sufficient to restore bile acid absorption and homeostasis after ileocaecal resection (ICR).


METHODS
Bile acid homeostasis was characterised in non-surgical, sham or ICR mice using two recombinant Gata4 models in which Asbt expression is induced to different levels.


RESULTS
Reduction of intestinal GATA4 activity resulted in an induction of ASBT expression, bile acid absorption and expression of bile acid-responsive genes in proximal small intestine, and a reduction of luminal bile acids in distal small intestine. While faecal bile acid excretion and bile acid pool size remained unchanged, the bile acid pool became more hydrophilic due to a relative increase in tauro-beta-muricholate absorption. Furthermore, proximal induction of Asbt in both Gata4 mutant models corrected ICR-associated bile acid malabsorption, reversing the decrease in bile acid pool size and increase in faecal bile acid excretion and hepatic cholesterol 7alpha-hydroxylase expression.


CONCLUSIONS
Reduction of intestinal GATA4 activity induces bile acid absorption in proximal small intestine without inducing major changes in bile acid homeostasis. This induction is sufficient to correct bile acid malabsorption caused by ICR in mice.
Beuling
Eva
E
GI/Cell Biology, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA.
Kerkhof
Ilona M
IM
Nicksa
Grace A
GA
Giuffrida
Michael J
MJ
Haywood
Jamie
J
aan de Kerk
Daniel J
DJ
Piaseckyj
Christina M
CM
Pu
William T
WT
Buchmiller
Terry L
TL
Dawson
Paul A
PA
Krasinski
Stephen D
SD
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D004195:Disease Models, Animal; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D007408:Intestinal Absorption / Q000235:genetics / Q000502:physiology*; D007421:Intestine, Small / Q000378:metabolism* / Q000601:surgery; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D013656:Taurocholic Acid / Q000031:analogs & derivatives / Q000378:metabolism
D001647:Bile Acids and Salts; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; C037351:tauromuricholic acid; D013656:Taurocholic Acid