Bile acids are the major determinant and
driving force for the generation of
bile flow.
Bile acid transport across the canalicular membrane is primarily an ATP-dependent process. The predominant transporter is the
bile salt excretory pump (BSEP,
ABCB11), a member of the
adenosine triphosphate-binding cassette (ABC) family of transporters. Regulatory mechanisms that can coordinate the genes encoding
bile acid transport proteins are critically important to avoid
hepatocyte damage from intracellar accumulation of
bile acids.
Bile salts are natural ligands for several
nuclear hormone receptors expressed in
liver and
intestine.
Nuclear receptors are
transcription factors that bind specific ligands such as
bile acids and regulate
gene expression according to the
metabolic requirements of the cell. In
cloning of the BSEP gene, we found a
binding site in the
promoter for the
farnesoid X receptor (FXR), a
nuclear receptor for
bile acids. FXR activity requires heterodimerization with the 9-cis
retinoid receptor (
RXR alpha), and when bound by
bile acids and retinoic acid, the complex effectively activates the transcription of BSEP.There is a growing body of evidence for the
activation of
nuclear hormone receptors through the remodeling of
chromatin by
histone modification involving
acetylation, in concert with
methylation of H3 and H4
histones. We have recently demonstrated a role for the coactivator-associated
arginine methyltransferase 1 (
CARM1), as a
coactivator of the FXR/
RXR receptor and regulator of FXR responsive genes such as BSEP.
Chromatin immunoprecipitation showed that the
bile acid-dependent
activation of the human BSEP is associated with a simultaneous increase of FXR and
CARM1 occupation of the BSEP
promoter. The increased occupation of the BSEP locus by
CARM1 also corresponds with the increased deposition of Arg-17
methylation and Lys-9
acetylation of
histone H3 within the FXR DNA-binding element of BSEP.Our work on the role of
nuclear receptors in regulation of
bile acid homeostasis has
led to an increased understanding of the
pathogenesis of the disorder,
progressive familial intrahepatic cholestasis, type 1 (PFIC1) or Byler disease. The gene
mutated in PFIC1 is called FIC1 and codes for a type IV
P-type ATPase whose function is unknown. Increased ileal apical sodium-dependent
bile acid transporter
messenger RNA (
mRNA) expression was detected in 3 patients with PFIC1. Ileal FXR and short heterodimer partner (an
inhibitory nuclear receptor)
messenger RNA levels were reduced in the same 3 patients. In studies of cells after antisense-mediated
knock-down of endogenous FIC1, the activity of the ileal apical
bile acid transporter
promoter was enhanced, whereas the activities of the human FXR and BSEP
promoters were reduced. Nuclear but not
cytoplasmic localization of FXR is markedly decreased in FIC1-negative cells, indicating that FIC1 is necessary for
posttranslational modifications necessary for the nuclear
translocation of FXR. This defect leads to enhanced ileal
bile salt uptake and
impaired canalicular
bile salt secretion by BSEP. In PFIC1, an increased load of
bile acids is retained in the
liver leading to
cholestasis and progressive
liver injury.
