Functional Analysis of Liver Receptor Homolog-1 and Farnesoid X Receptor in Enterohepatic Physiology
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Liver receptor homolog-1 (LRH-1), an orphan nuclear receptor, and farnesoid X receptor (FXR), a bile acid receptor, are both highly expressed in liver and intestine, where they regulate bile acid homeostasis. To gain further insight into their biological actions, we investigated their function in vivo using gain-of-function and loss-of-function strategies. For LRH-1, three different experimental approaches were used. First, we generated and analyzed mice deficient for LRH-1 in either hepatocytes or intestinal epithelium. These tissue-specific knockout mice had altered expression of a large number of genes involved in bile acid metabolism. Furthermore, there was a marked change in the composition of the bile acid pool in mice lacking LRH-1 in hepatocytes. In a second experimental approach, a constitutively-active form of LRH-1 (VP16LRH-1) was expressed in the intestine of transgenic mice. The intestines of these mice were profoundly enlarged due to alterations in pathways controlling proliferation and apoptosis. In a third experimental approach, the effect of LRH-1 on early developmental decisions was examined in Xenopus laevis. In animal cap explant assays, LRH-1 induced early molecular markers of endoderm differentiation. Taken together, the Xenopus laevis and mouse studies reveal the diverse roles that LRH-1 plays during development and in adult physiology, including effects on endoderm formation, intestinal proliferation, and bile acid homeostasis. FXR regulates bile acid homeostasis through actions in both liver and intestine. In studies designed to probe for additional actions, we found that FXR has an important role in preventing the overgrowth of bacteria in the small intestine. In summary, these studies reveal the diverse processes regulated by the nuclear receptors LRH-1 and FXR and their profound impact on enterohepatic physiology.