Compromised Intestinal Lipid Absorption in Mice with a Liver-Specific Deficiency of Liver Receptor Homolog 1

Abstract

Bile acids (BAs) are water-soluble end products from cholesterol metabolism and are essential for efficient absorption of dietary lipids. By using targeted somatic mutagenesis of the nuclear receptor liver receptor homolog 1 (LRH-1) in mouse hepatocytes, we demonstrate here that LRH-1 critically regulates the physicochemical properties of BAs. The absence of LRH-1 and subsequent deficiency of Cyp8b1 eliminate the production of cholic acid and its amino acid conjugate taurocholic acid and increase the relative amounts of less amphipathic BA species. Intriguingly, while the expression of Cyp8b1 is almost extinguished in the livers of mice that lack LRH-1, the expression of the rate-limiting enzyme of BA synthesis, i.e., Cyp7a1, remains unchanged. The profound remodeling of the BA composition significantly reduces the efficacy of intestinal absorption of lipids and reuptake of BAs and facilitates the removal of lipids from the body. Our studies unequivocally demonstrate a pivotal role for LRH-1 in determining the composition of BAs, which, in turn has major consequences on whole-body lipid homeostasis.

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.…”

“…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.…”

Lowering Bile Acid Pool Size with a Synthetic Farnesoid X Receptor (FXR) Agonist Induces Obesity and Diabetes through Reduced Energy Expenditure

“…TG, free fatty acids, and total cholesterol in the 3T3-L1 cells and liver were extracted by the classical Folch method (24) and measured as described previously (17). BAs in enterohepatic organs of fed mice were determined as described previously (25,26).…”

ALOX5AP Overexpression in Adipose Tissue Leads to LXA4 Production and Protection Against Diet-Induced Obesity and Insulin Resistance

“…For determination of bile acid (BA) excretion rate, feces from individually housed mice were collected during a 24-h period and dried for 1 h at 70°C. The extraction was performed in 2 mL chloroform:methanol (2:1) following a method previously described (30). BAs from feces and from plasma were measured enzymatically (Randox Laboratory, Crumlin, U.K.).…”