Bile Acids: Natural Ligands for an Orphan Nuclear Receptor

Abstract

Bile acids regulate the transcription of genes that control cholesterol homeostasis through molecular mechanisms that are poorly understood. Physiological concentrations of free and conjugated chenodeoxycholic acid, lithocholic acid, and deoxycholic acid activated the farnesoid X receptor (FXR; NR1H4), an orphan nuclear receptor. As ligands, these bile acids and their conjugates modulated interaction of FXR with a peptide derived from steroid receptor coactivator 1. These results provide evidence for a nuclear bile acid signaling pathway that may regulate cholesterol homeostasis.

The apical conjugate efflux pump ABCC2 (MRP2)

“…In addition, a hormone response element in the rat Abcc2 promoter (ER-8) was identified, which is bound by heterodimers of the retinoid X receptor α (RXRα, NR2B1 [129]) with the ligand-activated transcription factors farnesoid X receptor (FXR, NR1H4), pregnane X receptor (PXR, NR1I2), or constitutive androstane receptor (CAR, NR1I3) [73]. These nuclear receptors are, for example, activated by bile acids via FXR [132] by various xenobiotics such as the antibiotic rifampicin, the synthetic glucocorticoid dexamethasone, and pregnenolone 16α-carbonitrile via PXR [8, 41,85], or by phenobarbital via CAR [161]. Knowledge of the presence of the hormone response element ER-8 in the rat Abcc2 promoter [73] may now explain studies which describe the induction of Abcc2 mRNA and Abcc2 protein in primary cultures of rat hepatocytes by a number of xenobiotics, including the carcinogen 2-acetylaminofluorene, the anticancer drug cisplatin, the antifungal agent clotrimazole, the antibiotic cycloheximide, dexamethasone, the chemopreventive agents oltipraz and sulforaphane, phenobarbital, and pregnenolone 16α-carbonitrile [23, 73,75,98,137].…”

Quantification of the 15 major human bile acids and their precursor 7α-hydroxy-4-cholesten-3-one in serum by liquid chromatography–tandem mass spectrometry

“…Moreover, their emulsifying properties are essential for digestion of dietary fat and lipophilic vitamins. In the last decade, bile acids were additionally discovered to be natural ligands of the farnesoid X receptor (FXR) [1][2][3], a nuclear transcription factor through which they regulate their own biosynthesis via a negative feedback. Moreover, it is now well established that FXR activation by bile acids results in the regulation of various genes involved not solely in bile acid homeostasis but also in cholesterol, triglyceride and glucose metabolism [4][5][6][7][8][9].…”

Association between farnesoid X receptor expression and cell proliferation in estrogen receptor-positive luminal-like breast cancer from postmenopausal patients

“…The findings outlined above prompted us to examine the effect of the primary bile acid chenodeoxycholic acid (CDCA), the most potent endogenous ligand/activator of FXR [4], on the proliferation of MCF-7 and MDA-MB-231 cells cultured in steroid-free medium (SFM) supplemented or not with estrogen (Fig. 3a).…”

“…In subsequent studies, FXR was deorphanized by the identification of bile acids (in particular chenodeoxycholic acid, CDCA) as cognate ligands [2][3][4]. Presently, FXR is considered as a member of the metabolic nuclear receptor family [5].…”