Bile acid retention and activation of endogenous hepatic farnesoid-X-receptor in the pathogenesis of fatty liver disease in ob/ob-mice.
The nuclear bile acid receptor FXR (farnesoid-X-receptor) has recently been implicated in the pathophysiology of non-alcoholic fatty liver disease because selective FXR-agonists improve glucose and lipid metabolism in rodent models of obesity. However, the regulation of FXR and other relevant nuclear receptors as well as their lipogenic target genes in fatty liver is still not revealed in detail. Livers were harvested from 14-week-old male ob/ob mice and wild-type controls. Serum bile acids were quantified by radioimmunoassay. mRNA and protein expression of transporters and nuclear receptors was analyzed by reverse transcriptase-polymerase chain reaction and Western blotting, whereas DNA binding to the IR-1 element was examined by electrophoretic mobility shift assay. In this study we show: (i) bile acid retention in ob/ob mice, (ii) a resulting FXR upregulation and binding to the IR-1 element in ob/ob animals and (iii) concomitant activation of the fatty acid synthase as a potential lipogenic FXR target gene in vivo. The present study suggests a potential role of hepatic bile acid retention and FXR activation in the induction of lipogenic target genes. Differences between intestinal and hepatic FXR could explain apparent contradictory information regarding its effects on fatty liver disease.
Martin
Ina V
IV
Department of Internal Medicine III, University Hospital Aachen, Germany.
Schmitt
Johannes
J
Minkenberg
Alexander
A
Mertens
Joachim C
JC
Stieger
Bruno
B
Mullhaupt
Beat
B
Geier
Andreas
A
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated