Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1870, Issue 1, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbadis.2023.166870
Keywords
FGF21; Bile acids; Cholestasis; Mdr2 deficiency; FGFR4; JNK
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Cholestasis is a pathological process that leads to liver injury and diseases, and the liver-secreted hormone FGF21 acts as a signaling molecule to regulate the synthesis of bile acids, thereby alleviating cholestasis-induced damage.
Cholestasis is characterized by hepatic accumulation of cytotoxic bile acids (BAs), which often subsequently leads to liver injury, inflammation, fibrosis, and liver cirrhosis. Fibroblast growth factor 21 (FGF21) is a liversecreted 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 caused by alpha-naphthylisothiocyanate (ANIT) treatment and Mdr2 deficiency. 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.
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