Neohesperidin Exerts Lipid-Regulating Effects in vitro and in vivo via Fibroblast Growth Factor 21 and AMP-Activated Protein Kinase/Sirtuin Type 1/Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1α Signaling Axis

Abstract

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 HepG₂ 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 HepG₂ 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 1α (PGC-1α) axis or related molecules, was improved by NHP in HepG₂ 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-1α signaling axis.

The link between the AMPK/SIRT1 axis and a flavonoid‐rich extract of Citrus bergamia juice: A cell‐free, in silico, and in vitro study

“…Oliva and co‐workers demonstrated that the chronic treatment of NRG in ethanol‐fed male Wistar rats increased SIRT1 at both gene and protein level (Oliva et al, ). NHP was found to enhance the expression of SIRT1 both in vitro and in vivo, in free fatty acids‐induced lipid‐accumulated HepG2 cells and chronically diet‐induced obese (DIO) model mice, respectively (Wu et al, ). Regarding HSP and NER, this is the first report on their effect on SIRT1.…”

“…Some flavonoids assessed here have been studied for their properties on activating AMPK pathway. The treatment with NAR (Zygmunt, Faubert, MacNeil, & Tsiani, ), NRG (Sui, Xiao, Lu, & Sun, ), or NHP (Wu et al, ) was shown to positively act on AMPK both in vitro and in vivo models. HSP and NER were not investigated in these regards.…”

“…Some flavonoids assessed here have been studied for their properties on activating AMPK pathway. The treatment with NAR(Zygmunt, Faubert, MacNeil, & Tsiani, 2010), NRG(Sui, Xiao, Lu, & Sun, 2018), or NHP(Wu et al, 2017) was FIGURE 7 AMPK is implied in the activation of SIRT1 induced by BJe. THP-1 cells were treated with BJe or AICAR for 1 h, prior adding lipopolysaccharide (LPS).…”

The effect of aerobic training with Citrus aurantium L. on SIRT1 and PGC-1α gene expression levels in the liver tissue of elderly rats

“…In the present study, the expression of liver PGC-1α increased significantly after CA consumption and a combination of aerobic training and CA. The results of a study showed that the glycosidase flavonoid in citrus fruits can activate the AMPK-SIRT1-PGC-1α pathway and thus play a role in controlling fat metabolism (29). Naringin has also been shown to increase PGC-1α, CPT1 and adiponectin expression (30).…”

8 Weeks of 2s-Hesperidin Supplementation Improves Power Output at Estimated Functional Threshold Power and Maximum Power in Amateur Cyclist

“…The mechanisms by which chronic intake of hesperidin may improve performance are associated with increased activation of AMP-activated protein kinase (AMPK) [19,20] and nuclear respiratory factor 2 (NRF2) [6], leading to improved mitochondrial biogenesis and antioxidant status, respectively [21,22]. In addition, hesperidin has the ability to improve nitric oxide synthesis (NO) [23], which may improve glucose utilization in exercise and increase blood flow to the muscles, promoting an increase in nutrient and oxygen delivery to the muscle [24].…”