Mangiferin Ameliorates HFD-Induced NAFLD through Regulation of the AMPK and NLRP3 Inflammasome Signal Pathways

Abstract

Nonalcoholic fatty liver disease (NAFLD) is closely related to glycolipid metabolism and liver inflammation. And there is no effective drug approved for its clinical therapy. In this study, we focused on mangiferin (Man) and explored its effects and mechanisms on NAFLD treatment based on the regulation of glycolipid metabolism and anti-inflammatory in vivo and in vitro. The results exhibited that Man can significantly attenuate liver injury, insulin resistance, and glucose tolerance in high-fat diet- (HFD-) induced NAFLD mice and significantly reduce fat accumulation and inflammation in hepatic tissue of NAFLD mice. The transcriptome level RNA-seq analysis showed that the significantly different expression genes between the Man treatment group and the HFD-induced NAFLD model group were mainly related to regulation of energy, metabolism, and inflammation in liver tissue. Furthermore, western blots, real-time PCR, and immunohistochemistry experiments confirmed that Man significantly activated the AMPK signal pathway and inhibited NLRP3 inflammasome activation and pyroptosis in NAFLD mice. In in vitro cell experiments, we further confirmed that Man can promote glucose consumption and reduce intracellular triglyceride (TG) accumulation induced by free fatty acids in HepG2 cells and further that it can be blocked by AMPK-specific inhibitors. Western blot results showed that Man upregulated p-AMPKα levels and exhibited a significant AMPK activation effect, which was blocked by compound C. At the same time, Man downregulated the expression of NLRP3 inflammasome-related proteins and inhibited the activation of NLRP3 inflammasome, alleviating cell pyroptosis and inflammation effects. These results indicate that Man anti-NAFLD activity is mediated through its regulation of glucolipid metabolism by AMPK activation and its anti-inflammatory effects by NLRP3 inflammasome inhibition. Our study indicates that Man is a promising prodrug for the therapy of NAFLD patients.

Metformin suppresses foam cell formation, inflammation and ferroptosis via the AMPK/ERK signaling pathway in ox‑LDL‑induced THP‑1 monocytes

“…Combined with the results of the current study, it is hypothesized that metformin inhibits lipid accumulation by decreasing induction of ferroptosis in ox-LDL-stimulated macrophages. The AMPK signaling pathway is a major intracellular energy metabolism pathway, which serves a protective effect on atherosclerosis by inhibiting inflammation, regulating lipid metabolism, antioxidant activity, as well as suppressing immune responses (39)(40)(41). In addition, The ERK/MAPK signaling pathway serves an important role in the process of atherosclerosis (42).…”

Nootkatone, a Sesquiterpene Ketone From Alpiniae oxyphyllae Fructus, Ameliorates Metabolic-Associated Fatty Liver by Regulating AMPK and MAPK Signaling

“…AMPK activation in the liver is beneficial for glucose consumption, lipid oxidative decomposition, and body energy provision. Many AMPK agonists, such as mangiferin ( Yong, Ruiqi et al, 2021 ), berberine ( Zhu, Bian et al, 2019 ), and metformin ( Zamani-Garmsiri, Hashemnia et al, 2021 ), are considered potential drugs for MAFLD treatment. The results of this study are the first to demonstrate that Nok can improve MAFLD based on activation of hepatic AMPK in vitro and in vivo .…”

“…Total RNA was extracted, and quality was assessed by integrity. Relevant sample processing, sequencing, and data analysis methods were described in our previous research ( Yong, Ruiqi et al, 2021 ).…”

Plant-derived bioactive compounds regulate the NLRP3 inflammasome to treat NAFLD

“…A study indicated that body weight, liver weight, TC, TG, ALT, and AST were reduced after treatment with Man, while NLRP3, caspase-1, IL-1β, and GSDMD expression were downregulated in vivo and in vitro . These results indicated that the anti-NAFLD activity of Man is mediated by its anti-inflammatory effects via NLRP3 inflammasome inhibition ( Yong, Ruiqi et al, 2021 ).…”