Liver Receptor Homologue-1 Mediates Species- and Cell Line-specific Bile Acid-dependent Negative Feedback Regulation of the Apical Sodium-dependent Bile Acid Transporter

Abstract

Intestinal reclamation of bile salts is mediated in large part by the apical sodium-dependent bile acid transporter (ASBT). The bile acid responsiveness of ASBT is controversial. Bile acid feeding in mice results in decreased expression of ASBT protein and mRNA. Mouse but not rat ASBT promoter activity was repressed in Caco-2, but not IEC-6, cells by chenodeoxycholic acid. A potential liver receptor homologue-1 (LRH-1) cis-acting element was identified in the bile acid-responsive region of the mouse but not rat promoter. The mouse, but not rat, promoter was activated by LRH-1, and this correlated with nuclear protein binding to the mouse but not rat LRH-1 element. The short heterodimer partner diminished the activity of the mouse promoter and could partially offset its activation by LRH-1. Interconversion of the potential LRH-1 cis-elements between the mouse and rat ASBT promoters was associated with an interconversion of LRH-1 and bile acid responsiveness. LRH-1 protein was found in Caco-2 cells and mouse ileum, but not IEC-6 cells or rat ileum. Bile acid response was mediated by the farnesoid X receptor, as shown by the fact that overexpression of a dominant-negative farnesoid X-receptor eliminated the bile acid mediated down-regulation of ASBT. In addition, ASBT expression in farnesoid X receptor null mice was unresponsive to bile acid feeding. In summary cell line-and speciesspecific negative feedback regulation of ASBT by bile acids is mediated by farnesoid X receptor via small heterodimer partner-dependent repression of LRH-1 activation of the ASBT promoter.Reclamation of bile salts by the intestine is primarily mediated by the apical sodium-dependent bile acid transporter (ASBT) 1 located in the terminal ileum (1, 2). The bile acid responsiveness of ASBT expression, which is of fundamental importance to both cholesterol metabolism and cholestatic liver disease, is a matter of on-going controversy (3). Conflicting results have been observed in a number of laboratories, where experimental methodologies and animal species have been variable (4 -15). Positive (5, 7, 9, 11, 13-15), negative (4,6,8,12,15), and no (10) feedback regulation have been observed. Bile acid homeostasis has been perturbed by bile acid (4, 6, 8 -10, 12), sequestrant (4, 6, 8, 10), or cholesterol (10, 13, 14) feeding; by common bile duct ligation (7,10,11,15) or diversion (5, 9, 11); and by genetic modification of bile acid biosynthesis (12). Investigations have been carried out in rats (4, 5, 7, 9 -11, 15), mice (8, 12), guinea pigs (4, 6), and rabbits (13,14). Bile acid transport has been measured using intact intestine (4, 6, 11) and brush border membrane vesicles (5, 7, 9, 10, 15). ASBT expression has been quantified at the level of protein (9 -15) and messenger RNA (8,9,11,15). The complexity of the current literature reflects the difficulties of in vivo assessment of a transport system that is part of a highly integrated and tightly regulated metabolic pathway. The molecular mechanisms of bile acid responsiveness have been eluci...

Bile Acids Induce Ileal Damage During Experimental Necrotizing Enterocolitis

“…Previous research has shown that unlike rabbits, mice, and human beings, the rat ASBT gene is not regulated via a negative feedback mechanism by BAs.49 -53 BA responsiveness of ASBT is mediated by FXR-dependent activation of small heterodimer partner and subsequent inhibition of liver receptor homologue-1.52 , 53 The rat ASBT promoter lacks a functional liver receptor homologue-1 cis-acting element, and rat ileum does not express the liver receptor homologue-1 protein. 54 Our finding that ASBT protein levels are not increased in neonatal rats gavaged with BAs is consistent with these previous studies. It is compelling, therefore, that in our studies neonatal rats with NEC have statistically significantly increased ileal ASBT in conjunction with increased levels of ileal BA.…”

The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships

“…Furthermore, Asbt expression is regulated by bile acids through an activation of the nuclear farnesoid X receptor FXR. However, whereas in rabbits, mice and humans Asbt expression is under negative-feedback control by bile acids (Chen et al 2003;Neimark et al 2004;Li et al 2005), in rats Asbt expression was not regulated by alterations of ileal bile acid concentration (Arrese et al 1998). This could be explained by the absence of the liver receptor homologue-1 (LRH-1) transcription binding site in the rat Asbt promoter, by which FXR regulates Asbt expression in rabbits and mice (Chen et al 2003;Li et al 2004).…”

The Fetoprotein Transcription Factor (FTF) Gene Is Essential to Embryogenesis and Cholesterol Homeostasis and Is Regulated by a DR4 Element

“…FTF in the Adult-Converging evidence suggests that FTF basically operates the enterohepatic cholesterol/BA cycle by activating liver BA production and export via CYP7A1 and mrp3 (14 -17,34), intestinal BA absorption via ASBT (21), and BA reentry from intestinal cells into portal blood via mrp3 (20). Short term overexpression of hepatic FTF in transgenic TgF35 mice provides compelling in vivo support for the activating effect of FTF on CYP7A1 and SHP.…”

“…A model emerged whereby FTF would act as a "competence" factor driving the BA pathway, subject to negative feedback regulation by interaction of FTF with orphan receptor SHP, activated by the BA receptor FXR and by FTF itself (15,16,18,19). Additional reports associated further FTF action with membrane transporters of the enterohepatic BA recycling system (20,21) and with pancreatic cholesterol esterase (22), all of which pointing to an important systemic role for FTF in adult cholesterol/BA homeostasis.…”