Activating Adenosine Monophosphate-Activated Protein Kinase Mediates Fibroblast Growth Factor 1 Protection From Nonalcoholic Fatty Liver Disease in Mice.
Hepatology
; 73(6): 2206-2222, 2021 06.
Article
em En
| MEDLINE
| ID: mdl-32965675
ABSTRACT
BACKGROUND AND AIMS:
Fibroblast growth factor (FGF) 1 demonstrated protection against nonalcoholic fatty liver disease (NAFLD) in type 2 diabetic and obese mice by an uncertain mechanism. This study investigated the therapeutic activity and mechanism of a nonmitogenic FGF1 variant carrying 3 substitutions of heparin-binding sites (FGF1â³HBS ) against NAFLD. APPROACH ANDRESULTS:
FGF1â³HBS administration was effective in 9-month-old diabetic mice carrying a homozygous mutation in the leptin receptor gene (db/db) with NAFLD; liver weight, lipid deposition, and inflammation declined and liver injury decreased. FGF1â³HBS reduced oxidative stress by stimulating nuclear translocation of nuclear erythroid 2 p45-related factor 2 (Nrf2) and elevation of antioxidant protein expression. FGF1â³HBS also inhibited activity and/or expression of lipogenic genes, coincident with phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and its substrates. Mechanistic studies on palmitate exposed hepatic cells demonstrated that NAFLD-like oxidative damage and lipid accumulation could be reversed by FGF1â³HBS . In palmitate-treated hepatic cells, small interfering RNA (siRNA) knockdown of Nrf2 abolished only FGF1â³HBS antioxidative actions but not improvement of lipid metabolism. In contrast, AMPK inhibition by pharmacological agent or siRNA abolished FGF1â³HBS benefits on both oxidative stress and lipid metabolism that were FGF receptor (FGFR) 4 dependent. Further support of these in vitro findings is that liver-specific AMPK knockout abolished therapeutic effects of FGF1â³HBS against high-fat/high-sucrose diet-induced hepatic steatosis. Moreover, FGF1â³HBS improved high-fat/high-cholesterol diet-induced steatohepatitis and fibrosis in apolipoprotein E knockout mice.CONCLUSIONS:
These findings indicate that FGF1â³HBS is effective for preventing and reversing liver steatosis and steatohepatitis and acts by activation of AMPK through hepatocyte FGFR4.
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Base de dados:
MEDLINE
Assunto principal:
Fator 1 de Crescimento de Fibroblastos
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Receptor Tipo 4 de Fator de Crescimento de Fibroblastos
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Fator 2 Relacionado a NF-E2
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Proteínas Quinases Ativadas por AMP
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Hepatopatia Gordurosa não Alcoólica
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article