期刊
BIOCHEMICAL PHARMACOLOGY
卷 192, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2021.114678
关键词
Fibroblast growth factor 21 (FGF21); COX2; ALOX5; GPX4; Oxidative stress; iNOS
资金
- National Institutes of Alcoholism and Alcohol Abuse [R01AA024723]
- West Virginia IDeA Network of Biomedical Research Excellence (WV-INBRE) program - National Institute of General Medical Sciences (NIGMS) [P20GM103434]
FGF21 is mainly regulated by PPARα in liver, providing protection against ALD. While liver-specific FGFR1 abrogation had no effect on ALD, adipose tissues highly express FGFR1. In mice experiments, WY-14,643 inhibits alcoholic fatty liver through FGFR1-dependent regulation of adipose tissue mass and fat mobilization to the liver.
Fibroblast growth factor 21 (FGF21) is mainly regulated by peroxisome proliferator-activated receptor alpha (PPAR alpha) in liver. The PPAR alpha-FGF21 axis protects against alcohol-related liver disease (ALD). FGF21 exerts its effect via FGF receptor 1 (FGFR1). However, liver specific FGFR1 abrogation had no effect on ALD. Adipose tissues highly express FGFR1. When adipocyte specific FGFR1 knockout (fgfr1adipoQ-cre) mice and corresponding normal control (fgfr1fl/fl) mice were fed with Lieber-DeCarli ethanol liquid diet for 3 weeks, liver triglyceride (TG) accumulation was increased in the fgfr1fl/fl mice to a greater extent than in the fgfr1adipoQ-cre mice. When PPAR alpha agonist WY14,643 was added in the liquid ethanol diet at 10 mg/L, the ethanol-induced liver TG accumulation was blunted in the fgfr1fl/fl mice but not in the fgfr1adipoQ-cre mice. There was no significant difference in WY-14,643induced fatty acid oxidation, ethanol metabolism, and oxidative stress between the fgfr1fl/fl and fgfr1adipoQ-cre mice. Interestingly, adipose atrophy was induced by WY-14,643 in the fgfr1adipoQ-cre mice but not in the fgfr1fl/fl mice. Serum free fatty acid was also decreased by WY-14,643 in the fgfr1adipoQ-cre mice but not in the fgfr1fl/fl mice. These results suggest that WY-14,643 inhibits alcoholic fatty liver and regulates adipose tissue mass and fat mobilization from adipose tissues to liver in an adipocyte FGFR1-dependent manner.
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