Journal
PHARMACOLOGY
Volume 100, Issue 3-4, Pages 115-126Publisher
KARGER
DOI: 10.1159/000452492
Keywords
AMP-activated protein kinase/sirtuin type 1/peroxisome proliferator-activated receptor gamma coactivator 1 alpha; Dyslipidemia; Fibroblast growth factor 21; Lipid-regulating; Neohesperidin
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Funding
- National Natural Science Foundation of China [81202969]
- Natural Science Foundation of Zhejiang Province, China [LY13H260001]
- Science Technology Department of Zhejiang Province, China [2013C33158]
- Zhejiang Provincial Department of Education [Y201329974]
- National Project of Scientific and Technical Supporting Programs - Outstanding Youth Project of Natural Science Foundation of Zhejiang Province [LR16C200001]
- Fundamental Research Funds for the Central Universities [2014XZZX004]
- International Science and Technology Cooperation Program of China [2014DFE30050]
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The purpose of this study is to prove the lipid-regulating effects of neohesperidin (NHP) and explore the potential mechanisms related to fibroblast growth factor 21 (FGF21) and AMP-activated protein kinase (AMPK). Free fatty acids (FFAs)-induced lipid-accumulated HepG(2) cells, acutely egg yolk-induced dyslipidemia and chronically diet-induced obese (DIO) model mice were treated with NHP. Biochemical analyses were carried out to determine the lipid profiles. Western blotting and real-time PCR were employed to analyze FGF21, AMPK and the related proteins or mRNA expressions. Body weight and food intake were measured in DIO mice. siRNA or inhibitors of FGF21 or AMPK were utilized in further study. NHP showed potent hypolipidemic effect in HepG(2) cells loaded with FFAs and reversed the pathological changes of lipid in the acute or chronic dyslipidemia mouse model. It obviously improved the lipid profiles in plasma, liver and gastrocnemius muscles in DIO mice, and led to a significant body weight loss. Simultaneously, FGF21 protein expression or secretion, and AMPK/sirtuin type 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1 alpha(PGC-1 alpha) axis or related molecules, was improved by NHP in HepG(2) cells and/or DIO mice. Furthermore, the siRNA or inhibitor targeting FGF21 or AMPK rejected the triglyceride-lowering effect of NHP. In conclusion, NHP regulates lipid metabolism in vivo and in vitro via FGF21 and AMPK/SIRT1/PGC-1 alpha signaling axis. (C) 2017 S. Karger AG, Basel
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