Gut Liver.  2018 Jul;12(4):449-456. 10.5009/gnl17443.

Expression of Fibroblast Growth Factor 21 and β-Klotho Regulates Hepatic Fibrosis through the Nuclear Factor-κB and c-Jun N-Terminal Kinase Pathways

• Lee KJ
• Jang YO
• Cha SK
• Kim MY
• Park KS
• Eom YW
• Baik SK

• KMID: 2417312
• DOI: http://doi.org/10.5009/gnl17443

Abstract

BACKGROUND/AIMS
Fibroblast growth factor (FGF) 21 is associated with hepatic inflammation and fibrosis. However, little is known regarding the effects of inflammation and fibrosis on the β-Klotho and FGF21 pathway in the liver.
METHODS
Enrolled patients had biopsy-confirmed viral or alcoholic hepatitis. FGF19, FGF21 and β-Klotho levels were evaluated using enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and Western blotting. Furthermore, we explored the underlying mechanisms for this process by evaluating nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathway involvement in Huh-7 cells.
RESULTS
We observed that the FGF19 and FGF21 serum and mRNA levels in the biopsied liver tissue gradually increased and were correlated with fibrosis stage. Inflammatory markers (interleukin 1β [IL-1β], IL-6, and tumor necrosis factor-α) were positively correlated, while β-Klotho expression was negatively correlated with the degree of fibrosis. In Huh-7 cells, IL-1β increased FGF21 levels and decreased β-Klotho levels. NF-κB and JNK inhibitors abolished the effect of IL-1β on both FGF21 and β-Klotho expression. FGF21 protected IL-1β-induced growth retardation in Huh-7 cells.
CONCLUSIONS
These results indicate that the inflammatory response during fibrogenesis increases FGF21 levels and suppresses β-Klotho via the NF-κB and JNK pathway. In addition, FGF21 likely protects hepatocytes from hepatic inflammation and fibrosis.

Keyword

Fibroblast growth factor 21; β-Klotho; Interleukin-1beta; NF-kappa B; JNK

MeSH Terms

Blotting, Western
Enzyme-Linked Immunosorbent Assay
Fibroblast Growth Factors*
Fibroblasts*
Fibrosis*
Hepatitis, Alcoholic
Hepatocytes
Humans
Inflammation
Interleukin-1beta
Interleukin-6
JNK Mitogen-Activated Protein Kinases*
Liver
MAP Kinase Signaling System
Necrosis
NF-kappa B
Real-Time Polymerase Chain Reaction
RNA, Messenger
Fibroblast Growth Factors
Interleukin-1beta
Interleukin-6
JNK Mitogen-Activated Protein Kinases
NF-kappa B
RNA, Messenger