Z Gastroenterol 2019; 57(01): e17
DOI: 10.1055/s-0038-1677084
1. Basic Hepatology (Fibrogenesis, NPC, Transport)
Georg Thieme Verlag KG Stuttgart · New York

Altered Fgf21 response in alcohol induced “Acute-on-chronic liver injury” (ACLI) model

E Karatayli
1   Universität des Saarlandes, Klinik für Innere Medizin II, Homburg
,
G Christidis
1   Universität des Saarlandes, Klinik für Innere Medizin II, Homburg
,
RA Hall
1   Universität des Saarlandes, Klinik für Innere Medizin II, Homburg
,
SN Weber
1   Universität des Saarlandes, Klinik für Innere Medizin II, Homburg
,
S Dooley
2   Universität Heidelberg, Medizinische Fakultät, Mannheim
,
F Lammert
1   Universität des Saarlandes, Klinik für Innere Medizin II, Homburg
,
SC Karatayli
1   Universität des Saarlandes, Klinik für Innere Medizin II, Homburg
› Author Affiliations
Further Information

Publication History

Publication Date:
04 January 2019 (online)

 
 

    Background and Aims:

    The fibroblast growth factor (FGF) 21 acts as the main regulator of glucose and lipid homeostasis, and has recently been shown to have a potential role in bile acid metabolism. In this study, we aim to investigate FGF21 response in an ethanol induced acute on chronic liver injury (ACLI) model in Abcb4-/- mice, which is a reproducible model for chronic biliary liver disease.

    Method:

    Total RNA was extracted from liver tissue samples of 15 week-old wild type (WT) C57BL/6J and Abcb4 knock-out (KO) mice which were either fed with control diet (WT/Cont and KO/Cont groups) or liquid ethanol diet (5% v/v) followed by an acute ethanol binge (5 mg/kg) (WT/EtOH and KO/EtOH groups). Each group consisted of 16 mice (total n = 64). Fibrosis was assessed by hydroxyproline assay and quantified by a histomorphometric semi-automatic system for image analysis in Sirius red stainings. Inflammatory cells in liver were shown by hematoxylin-eosin (H&E) staining and identified by immunohistochemistry (IHC) staining for CD4, Cd11b, CD45 and F4/80. Liver specific mRNA levels of Fgf21, Fgf15, Fgfr1, Fgfr4, Klb, Srebf1, Cyp7a1, Fxr and Shp were evaluated using the 2-ΔΔCt method, in which Gapdh was used as internal control. ELISA was performed for plasma FGF15 and FGF21 levels. ANOVA followed by Bonferroni posthoc tests was performed. P < 0.05 was considered as significant.

    Results:

    Ethanol exposure significantly upregulated FGF21 response in WT and Abcb4-/- mice (p = 0.048 and 0.043, respectively) compared to their control diet fed counterparts, although no significant difference was found between genotypes. This elevation of FGF21 was also observed in plasma samples of alcohol challenged WT and Abcb4-/- mice with similar statistical significance (p = 0.040 and 0.048, respectively). No hepatic expression was observed for Fgf15, either in controls or in knock-outs. FGF15 plasma levels showed no difference between groups. Downregulation of Klb and Shp expressions reached significant levels only in ethanol challenged Abcb4-/- mice compared to control diet fed WT mice (p = 0.049 and p = 0.047, respectively). No significant difference was observed for Fxr, Srebf1, Fgfr1 and Fgfr4 expressions between groups. Hepatic expression level of Cyp7a1 was significantly downregulated in alcohol challenged WT and Abcb4-/- mice when compared to the WT control group (p = 0.009 and p = 0.009, respectively). The inflammatory infiltrates in the liver were shown to be predominated by portal inflammatory infiltrates composed of Cd45+ neutrophils, CD11b and CD4-positive lymphocytes and F4/80 positive macrophages in ethanol challenged knock-out mice.

    Conclusion:

    Chronic plus binge ethanol-feeding markedly suppressed hepatic expression levels of the rate-limiting enzyme CYP7A1 in bile acid metabolism, regardless of the mice genotype. Similarly, ethanol exposure has a significant effect on Fgf21 expression levels as well with an upregulation instead of downregulation, whereas Fgfr4 and FGF15 levels did not differ. Therefore, upon ethanol challenge, bile acid metabolism might be regulated by upregulation of FGF21 resulting in an inhibition of CYP7A1 through a metabolic pathway independent of FGF15. Moreover, our data suggests that, with relevance to the ACLI model, the presence of a chronic liver injury is required for Shp and Klb to be significantly downregulated by alcohol.


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