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Fibroblast growth factor 21 ameliorates cholestatic liver injury via a hepatic FGFR4-JNK pathway

ABSTRACT: Cholestasis is characterized by hepatic accumulation of cytotoxic bile acids (BAs), which often subsequentlyleads to liver injury, inflammation, fibrosis, and ultimately liver cirrhosis. Fibroblast growth factor 21 (FGF21) is a liver secreted hormone with pleiotropic effects on the homeostasis of glucose, lipid, and energy metabolism. However, whether hepatic FGF21 plays a role in cholestatic liver injury remains elusive. We found that serum and hepatic FGF21 levels were significantly increased in response to cholestatic liver injury. Hepatocyte-specific deletion of Fgf21 exacerbated hepatic accumulation of BAs, further accentuating liver injury. Consistently, administration of rFGF21 ameliorated cholestatic liver injury in α-naphthylisothiocyanate (ANIT)-treated and Mdr2 deficiency mice. Mechanically, FGF21 activated a hepatic FGFR4-JNK signaling pathway to decrease Cyp7a1 expression, thereby reducing hepatic BAs pool. Our study demonstrates that hepatic FGF21 functions as an adaptive stress-responsive signal to downregulate BA biosynthesis, thereby ameliorating cholestatic liver injury, and FGF21 analogs may represent a candidate therapy for cholestatic liver diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE240733 | GEO | 2023/08/19

REPOSITORIES: GEO

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mRNA Expression data from rats treated with ANIT or vehicle

Project description:Adult Sprague Dawley rats were treated i.g. with 50 mg/kg alpha-naphthylisothiocyanate (ANIT) or vehicle (corn oil). Hepatobiliary liver injury occurred at 24 h postdose in ANIT rats with repair at 120h. Livers were extracted from rats at 24h and 120 h post ANIT exposure. This study investigated differences in mRNA expression between the injury and repair phases in the context of ANIT exposure. 8 week male Sprague Dawley rats were administered ANIT or vehicle for quantification of hepatobiliary injury via clinical chemistry biomarkers and pathology between 6 and 168 h postdosing. Rats sacrificed at 24 h and 120h postdosing coincided with peak injury and injury resolution, respectively.

2015-08-26 | E-GEOD-72387 | biostudies-arrayexpress

mRNA Expression data from rats treated with ANIT or vehicle

2015-08-26 | GSE72387 | GEO

The G protein-coupled bile acid receptor TGR5 (Gpbar1) modulates endothelin-1 signalling in liver

Project description:TGR5 (Gpbar1) is a G protein-coupled receptor responsive to bile acids (BAs), which is expressed in different non-parenchymal cells of the liver, including biliary epithelial cells, liver-resident macrophages, sinusoidal endothelial cells (LSECs) and activated hepatic stellate cells (HSCs). Mice with targeted deletion of TGR5 are more susceptible towards cholestatic liver injury induced by cholic acid-feeding and bile duct ligation, resulting in a reduced proliferative response and increased liver injury. Conjugated lithocholic acid (LCA) represents the most potent TGR5 BA ligand and LCA-feeding has been used as a model to rapidly induce severe cholestatic liver injury in mice. Thus, TGR5 knockout (KO) mice and wildtype littermates were fed a diet supplemented with 1%LCA for 84 hours. Liver injury and gene expression changes induced by the LCA-diet revealed an enrichment of pathways associated with inflammation, proliferation and matrix remodelling. Knockout of TGR5 in mice caused upregulation of endothelin-1 (ET-1) expression in the livers. Analysis of TGR5-dependent ET-1 signalling in isolated LSECs and HSCs demonstrated that TGR5 activation reduces ET-1 expression and secretion from LSECs and triggers internalization of the ET-1 receptor in HSCs dampening ET-1 responsiveness. Thus, we identified two independent mechanisms by which TGR5 inhibits ET-1 signalling and modulates portal pressure.

2019-11-19 | GSE139075 | GEO

Gene expression analysis of FXR null, SHP null, and double FXR/SHP null mice

Project description:Bile acid (BA) homeostasis is maintained through a feedback loop operated by the nuclear hormone receptors FXR and SHP. Here we show that contrary to the current models placing FXR upstream of SHP in a linear regulatory pathway, the phenotypic consequence of the combined loss of both receptors is much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. This is highlighted by the dramatic elevation of hepatic and serum BA levels in the double knockout (DKO) mice as early as three weeks of age coupled with a commensurate increase in Cyp7A1 expression and alterations in BA homeostatic genes. In addition, we find several genes necessary for C21 steroid biosynthetic pathway as novel targets for FXR and SHP. The elevated BAs result in severe hepato-pathology but the DKO mice surprisingly do not develop complete liver failure and live for over a year. Their survival is accompanied by an adaptive proliferation of the resident liver progenitor cell population, known as oval cells. Overall, these data demonstrate that FXR and SHP function coordinately to maintain BA homeostasis, and identify DKO mice as a novel genetic model for juvenile cholestatic disorders and for oval cell activation. Liver samples collected from FXR-/-, SHP-/-, and FXR-/-/SHP-/- animals at 3 or 5 weeks were hybridized to Illumina mouse REF-8 v1.1 arrays in duplicate.

2010-12-10 | E-GEOD-20599 | biostudies-arrayexpress

The protective effect of celastrol in ANIT-induced cholestasis

Project description:Purpose: The goals of this study was to (1) evaluate the protective effect of celastrol on alpha-naphthylisothiocyanate (ANIT)-induced cholestasis and (2) which genes were recovered by celastrol. Methods:To investigate the protective effect of celastrol on ANIT-induced cholestasis, the WT mice were randomly assigned into two groups, respectively (n=3): (1) ANIT; (2) ANIT+Celastrol. ANIT+Celastrol group was orally treated with celastrol (10 mg/kg dissolved in 1% DMSO + 2% Tween 80 + 97% water) for 5 consecutive days. After celastrol was treated for 3 days, ANIT and ANIT+Celastrol groups were given a single oral dose of ANIT. All mice were killed 48 h after ANIT administration. Liver samples were harvested and frozen at -80 °C before analysis. Results: A total of 978 DEGs were identified. Large numbers of these DEGs were related to activation of SIRT1, which included increased FXR signaling and inhibition of PPARγ, nuclear factor-kappa B (NF-κB), and P53 signaling. Conclusions: Celastrol could protect ANIT-induced cholestasis by recovering disrupted Sirt1 level.

2018-02-09 | GSE110391 | GEO

Liver gene expression profile _ wild type_ CYP7A1 transgenic

Project description:Bile acids are not only physiological detergents facilitating nutrient absorption, but also signaling molecules regulating metabolic homeostasis. We reported recently that transgenic expression of CYP7A1 in mice stimulated bile acid synthesis and prevented Western diet-induced obesity, insulin resistance and hepatic steatosis. The aim of this experiment is to determine the impact of induction of hepatic bile acid synthesis on liver metabolism by determining hepatic gene expression profile in CYP7A1 transgenic mice. CYP7A1 transgenic mice and wild type control mice were fed either standard chow diet or high fat high cholesterol Western diet for 4 month. Hepatic gene expressions were measured by microarray analysis. Our results indicate that hepatic bile acid synthesis is closely linked to cholesterogenesis and lipogenesis, and maintaining bile acid homeostasis is improtant in hepatic metabolic homeostasis. Male aged matched (~ 12-14 weeks) CYP7A1 transgenic mice and their wild type control littermates were fed a standard chow diet or a high fat (42%) high cholesterol (0.2%) diet (Harlan Teklad #88137) for 4 month Four groups (4 mice/group) are included in the experiments: Group 1: WT _ Chow Group 2: CYP7A1-tg + chow Group 3: WT + Western diet Group 4: CYP7A1-tg _ Western diet Total liver mRNA was isolated with a RNeasy kit (Qiagen) and used for microarray analysis.

2013-08-15 | E-GEOD-38872 | biostudies-arrayexpress

Gene expression analysis of FXR null, SHP null, and double FXR/SHP null mice

2010-12-10 | GSE20599 | GEO

An ITRAQ-Based Quantitative Proteomics Analysis of the Hepatoprotective Effect of Melatonin on ANIT-Induced Cholestasis in Rats.

Project description:The aim of the present study was to investigate the therapeutic mechanism of the anti-cholestatic effects of melatonin against ANIT-induced liver injury in rats, and to screen for potential biomarkers of cholestasis through isobaric tags for relative and absolute quantitation (iTRAQ) quantitative proteomics.

2020-12-16 | PXD023155 | iProX

Prominin-1-expressing Hepatic Progenitor Cells Induce Fibrogenesis in Murine Cholestatic Liver Injury

Project description:Purpose: Cholestatic liver injury is associated with intrahepatic biliary fibrosis, which can progress to cirrhosis. Resident hepatic progenitor cells (HPCs) expressing Prominin-1 (Prom1/CD133) become activated and participate in the expansion of cholangiocytes known as the ductular reaction. Previously, we demonstrated that in biliary atresia, Prom1(+) HPCs are present within developing fibrosis and that null mutation of Prom1 significantly abrogates fibrogenesis. Here, we hypothesized that these activated Prom1-expressing HPCs promote fibrogenesis in cholestatic liver injury. Methods: Using Prom1CreERT2-nLacZ/+;Rosa26Lsl-GFP/+ mice, we traced the fate of Prom1-expressing HPCs in the growth of the neonatal and adult livers and in biliary fibrosis induced by bile duct ligation (BDL). Results: Prom1-expressing cell lineage labeling with Green Fluorescent Protein (GFP) on postnatal day 1 exhibited an expanded population as well as bipotent differentiation potential towards both hepatocytes and cholangiocytes at postnatal day 35. However, in the adult liver, they lost hepatocyte differentiation potential. Upon cholestatic liver injury, adult Prom1-expressing HPCs gave rise to both PROM1(+) and PROM1(-) cholangiocytes contributing to ductular reaction without hepatocyte or myofibroblast differentiation. RNA-sequencing analysis of GFP(+) Prom1-expressing HPC lineage revealed a persistent cholangiocyte phenotype and evidence of Transforming Growth Factor-b pathway activation. Conclusion: Our data indicate that Prom1-expressing HPCs promote biliary fibrosis by activation of myofibroblasts in cholestatic liver injury.

2020-06-30 | GSE144726 | GEO

Rapid increase of fibroblast growth factor 21 under protein malnutrition and its impact on growth and lipid metabolism

Project description:Protein malnutrition promotes hepatic steatosis, decreases insulin-like growth factor (IGF)-I production, and retards growth. In order to identify new molecules involved in such changes, we conducted DNA microarray analysis for liver samples of rats fed isoenergetic low protein diet for 8 hours, and identified fibroblast growth factor 21 (Fgf21) as one of the most strongly up-regulated genes under conditions of acute protein malnutrition (P<0.05, FDR<0.001). In addition, amino acid deprivation from the culture media increased Fgf21 mRNA levels in rat liver-derived RL-34 cells (P<0.01). Thus, it was suggested that amino acid limitation directly increases Fgf21 expression. FGF21 is a polypeptide hormone that regulates glucose and lipid metabolism. Using transgenic mice, FGF21 has also been shown to promote a growth hormone-resistant state and suppress IGF-I. Therefore, to further determine whether the up-regulation of Fgf21 under protein malnutrition causes hepatic steatosis and growth retardation following decrease in IGF-I, we fed isoenergetic low protein diet to Fgf21-knockout (KO) mice. Fgf21-KO did not rescue growth retardation and reduced plasma IGF-I concentration of mice fed the low-protein diet. Meanwhile, Fgf21-KO mice showed greater epididymal white adipose tissue weight as well as hepatic triglyceride and cholesterol levels under protein malnutrition (P<0.05). Taken together, we showed that protein deprivation directly increases Fgf21 expression. However, growth retardation and decreased IGF-I were not mediated by increased FGF21 expression under protein malnutrition. Furthermore, up-regulated FGF21 rather appears to have a protective effect against obesity and hepatic steatosis in protein malnourished animals. Livers of rats from 2 groups (control (15P) or low-protain (5P) diet fed groups), total of 6 samples (3 replicates for each group) were analyzed.

2015-01-15 | E-GEOD-64970 | biostudies-arrayexpress

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