Liver receptor homolog‐1 is critical for adequate up‐regulation of Cyp7a1 gene transcription and bile salt synthesis during bile salt sequestration

Abstract

Liver receptor homolog-1 (LRH-1) is a nuclear receptor that controls a variety of metabolic pathways. In cultured cells, LRH-1 induces the expression of CYP7A1 and CYP8B1, key enzymes in bile salt synthesis. However, hepatic Cyp7a1 mRNA levels were not reduced upon hepatocyte-specific Lrh-1 deletion in mice. The reason for this apparent paradox has remained elusive. We describe a novel conditional whole-body Lrh-1 knockdown (LRH-1-KD) mouse model to evaluate the dependency of bile salt synthesis and composition on LRH-1. Surprisingly, Cyp7a1 expression was increased rather than decreased under chowfed conditions in LRH-1-KD mice. This coincided with a significant reduction in expression of intestinal Fgf15, a suppressor of Cyp7a1 expression, and a 58% increase in bile salt synthesis. However, when fecal bile salt loss was stimulated by feeding the bile salt sequestrant colesevelam, Cyp7a1 expression was up-regulated in wildtype mice but not in LRH-1-KD mice (1593% in wildtype versus 19% in LRH-1-KD). This translated into an increase in bile salt synthesis of 1272% in wildtype versus 121% in LRH-1-KD mice. Conclusion: Our data provide mechanistic insight into a missing link in the maintenance of bile salt homeostasis during enhanced fecal loss and support the view that LRH-1 controls Cyp7a1 expression from two distinct sites, i.e., liver and ileum, in the enterohepatic circulation. (HEPATOLOGY 2011;53:2075-2085 B ile salts are synthesized from cholesterol exclusively in the liver by a complex multienzyme process. Crucial steps in the synthesis pathway comprise the addition of one or two hydroxyl groups to the sterol nucleus and the oxidative cleavage of the side chain of cholesterol, resulting in a highly amphipathic class of bile salt molecules. Bile salts are potent surfactants that solubilize phosphatidylcholine and cholesterol in bile and promote lipid absorption in the small intestine. Next to being the primary driving force for hepatic bile formation, the role in intestinal lipid digestion has long been thought to be the most important function of bile salts. 1 The landmark discovery of bile salts as endogenous ligands for the nuclear hormone receptor farnesoid X-receptor (FXR) and, more recently, for the G-protein-coupled receptor TGR5 has completely transformed the field of bile salt research. In addition to mediating the feedback control of bile salt synthesis, FXR influences many pathways involved in lipid metabolism and has recently also been implicated in control glucose metabolism. 2 TGR5 seems particularly important in regulating energy metabolism. 3 Accordingly, it is essential to fully understand the factors that regulate synthesis of the various types of bile salts. Liver receptor homolog-1 (LRH-1) has been implicated herein, but its exact role has remained Abbreviations: alpha-MCA, alpha-muricholate; beta-MCA, beta-

Induction of farnesoid X receptor signaling in germ-free mice colonized with a human microbiota

“…The expression of Cyp7a1 and Cyp8b1 is regulated by a negative feedback mechanism involving FXR and SHP in the liver (20)(21)(22). However, our finding that Cyp7a1 and Cyp8b1 are differently regulated is supported by several previous studies (7,(23)(24)(25)(26). The genes encoding the cytochrome enzymes involved in the alternative BA synthesis, sterol 27-hydroxylase (CYP27A1) and oxysterol 7--hydroxylase (CYP7B1), were unchanged after 2 weeks' colonization with mouse or human microbiota (Fig.…”

Reversible infertility in a liver receptor homologue-1 (LRH-1)-knockdown mouse model

“…However, some interesting differences and additional findings were observed. With respect to the liver, Shp and Scarb1 expression was reduced, but Cyp7a1 expression was unaffected (Mataki et al 2007;Lee et al 2008;Out et al 2011). Liver histology was normal and plasma liver parameters were not significantly changed (data not shown); these findings are in line with other studies of LRH-1-deficient mouse models.…”

“…In these models, LRH-1 was shown to affect Shp and Cyp8b1 expression in the liver, thereby reducing the amount cholic acid in the bile acid pool. In a more recent study, LRH-1 was shown to be critical for adequate regulation of Cyp7a1 under conditions of bile acid sequestration (Out et al 2011).…”

“…Compounds modulating the activity of LRH-1 could represent an attractive new therapy for multiple indications because LRH-1 has been implicated in the inflammatory response, tumour formation, bile acid homeostasis and fertility (Botrugno et al 2004;Schoonjans et al 2005;Mueller et al 2006;Venteclef et al 2006Venteclef et al , 2011Coste et al 2007;Mataki et al 2007;Duggavathi et al 2008;Lee et al 2008;Out et al 2011). The crystal structure of LRH-1 in complex with cofactor peptides reveals the presence of phospholipids in the ligand-binding domain, indicating that the activity of LRH-1 can potentially be modulated (Ortlund et al 2005;Burendahl et al 2008).…”

“…Analysis of several genetically engineered mouse models revealed an important role of LRH-1 in bile acid homeostasis and subsequent lipid absorption (Mataki et al 2007; Lee et al 2008;Out et al 2011). In these models, LRH-1 was shown to affect Shp and Cyp8b1 expression in the liver, thereby reducing the amount cholic acid in the bile acid pool.…”