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Mice with humanized FXR ligand-binding domain display distinct metabolic responses upon pharmacological FXR stimulation
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DOI：10.1016/j.jlr.2026.101088.png)
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Abstract
En 中文
Farnesoid-X-receptor (FXR), a bile acid (BA)-activated nuclear receptor, is a therapeutic target for cholestatic and metabolic liver diseases. However, species differences in BA metabolism and FXR signaling hamper translation from mice to humans. The human FXR ligand-binding domain (LBD) structurally differs from the murine LBD, potentially impacting pharmacological responses. Therefore, we generated mice with “humanized” FXR by replacing the murine LBD by the human LBD (FXR-hLBD) and assessed its impact on BA and cholesterol metabolism. Male and female FXR-hLBD mice on wild-type (WT) or Cyp2c70−/− backgrounds were compared with FXR-mLBD controls under non-stimulated conditions. Additionally, WT mice expressing FXR-mLBD or FXR-hLBD received either vehicle or obeticholic acid (OCA; 40 mg/kg/day, p.o.) for 7 days. FXR humanization did not alter hepatic or intestinal FXR expression levels. Under basal conditions, physiological parameters, liver pathology markers, and hepatic transcriptomes were similar between FXR-hLBD and FXR-mLBD mice on a WT C57BL/6J background and in mice with a human-like BA composition (Cyp2c70−/−). OCA did, however, elicit markedly stronger transcriptional responses in FXR-hLBD mice, including more pronounced suppression of hepatic BA synthesis genes and differential regulation of BA transporters. Intriguingly, pathways involved in cell proliferation and fibrogenesis were induced in FXR-hLBD mice. Furthermore, OCA lowered plasma cholesterol to a greater extent in FXR-hLBD than FXR-mLBD mice, primarily due to a reduction in HDL-cholesterol. FXR-hLBD mice resemble FXR-mLBD controls under basal conditions but exhibit enhanced responses to FXR agonism by OCA. This model may improve preclinical evaluation of FXR-targeting drugs in a translation-relevant context.
Keywords:
humanized mouse model
nuclear receptor
cytochrome P450
bile acid metabolism
cholesterol metabolism
obeticholic acid
liver
AF-1
activation function-1
AF-2
activation function-2
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ASCVD
atherosclerotic cardiovascular disease
AST
aspartate aminotransferase
BA
bile acid
BSA
bovine serum albumin
BSEP
bile salt export pump
BW
body weight
CA
cholic acid
CDCA
chenodeoxycholic acid
CDS
coding sequence
DBD
DNA-binding domain
DCA
deoxycholic acid
ER-2
everted repeat-2
FDR
False Discovery Rate
Fgf15/FGF19
fibroblast growth factor 15/19
FGFR4
FGF receptor 4
FPLC
fast protein liquid chromatography
FXR
farnesoid X receptor
GSEA
Gene Set Enrichment Analysis
H&E
hematoxylin & eosin
HDL-C
high-density lipoprotein cholesterol
Het
heterozygous
HI
hydrophobicity index
IR-1
inverted repeat-1
KI
knock-in
LBD
ligand-binding domain
LDL-C
low-density lipoprotein cholesterol
MASLD
metabolic dysfunction-associated steatotic liver disease
MCAs
muricholic acids
NP40
Nonidet P40
NTCP
taurocholate co-transporting polypeptide
OATP
organic anion transporting polypeptides
OCA
obeticholic acid
PBC
primary biliary cholangitis
PC
principal component
PCA
principal component analysis
PFIC
progressive familial intrahepatic cholestasis
PSC
primary sclerosing cholangitis
RXR
retinoid X receptor
sgRNA
single guide RNA
SHP
small heterodimer partner
SR-B1
scavenger receptor class B type I
SrFg
sirius red/fast green
TGR5
Takeda G protein-coupled receptor 5
UDCA
ursodeoxycholic acid
UPLC
ultra-high performance liquid chromatography
Veh
vehicle
VLDL
very low-density lipoprotein
WT
wild-type
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