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

Abstract

Metabolic-associated fatty liver disease (MAFLD) is becoming more common due to lifestyle changes. A long-term high-fat and high-glucose diet induces glycolipid metabolism disorders in the liver, which results in the development of MAFLD. To date, there is no specific clinically useful therapeutics for this disease. Natural products or synthetic compounds were screened and investigated to find effective agents for treating MAFLD. In this study, nootkatone (Nok), a natural sesquiterpene ketone isolated from Alpiniae oxyphyllae fructus, was explored for its potential to treat MAFLD, and underlying mechanisms were studied. Our results show that Nok dramatically ameliorated the disordered lipid and glucose metabolism in MAFLD mice, decreased fat accumulation in hepatic tissue, and improved liver injury. Inflammation, metabolic disorder, and oxidative stress were ameliorated in liver tissue based on RNA-seq transcriptome comparison between a Nok-treated group and an MAFLD model group. Furthermore, Nok significantly activated AMPK activity and inhibited MAPK activity, especially the p38 and JNK signaling pathways, in vivo based on western blot analysis. The pharmaceutical effects and potential signaling pathways impacted by Nok were also investigated in L02 cells. Nok significantly promoted the consumption of glucose and decreased the deposition of triglycerides in vitro. The p-AMPKα level was notably upregulated by Nok, indicating dramatic AMPK activation. In addition, Nok decreased the levels of p-ERK1/2, p-p38, and p-JNK. Nok also inhibited the activation of MAPK signaling and, thus, alleviated MAFLD development. Our results suggest that Nok may be useful in treating MAFLD. Nok may ameliorate MAFLD by regulating glycolipid metabolism disorders by activating AMPK and inhibiting MAPK activity. Collectively, this study suggests that Nok is an effective compound for the treatment of MAFLD.

Alpiniae oxyphyllae fructus improves production performance and egg quality of laying breeder hens by regulating reproductive hormones, antioxidant function, immunity and intestinal health

“…Similarly, significant reductions were observed in serum TC, TG, and GLU levels following AOP treatment ( Ghasemi and Nari, 2019 ). Nootkatone, mainly from Alpiniae Oxyphyllae Fructus , was shown to dramatically increase glucose consumption and decrease intracellular TG accumulation in L02 cells; this was supported by in vitro data in a study conducted by ( Yong et al, 2022 ). The incorporation of AOP into the diet at a concentration of 3 g/kg for laying hens was observed to have advantageous impacts on both the internal and external quality of eggs.…”

Liver fibrosis and MAFLD: the exploration of multi-drug combination therapy strategies

“…Up to now, there is no specific clinically useful therapy for MAFLD, thus some people try to screen and study natural products or synthetic compounds to find efficacious drugs for the treatment of MAFLD, such as the natural sesquiterpene ketone (Nok) ( 81 ), hydroxytyrosol (HXT), and vitamin E. Both HXT and vitamin E have good antioxidant properties ( 82 ), and oxidative stress is an influential factor that induces HSCs to activate and leads to liver fibrosis ( 83 ). HSCs can be activated by tumor growth factor TGF-β, leading to a significant increase in proliferation rate ( 84 ).…”

Production, Function, and Applications of the Sesquiterpenes Valencene and Nootkatone: a Comprehensive Review

“…In vitro study also demonstrated that nootkatone increased glucose consumption and decreased triglyceride (TG) concentration. 164 In addition, a clinical study showed that the consumption of fresh grapefruit (active component being nootkatone) or grapefruit juice could produce significant reductions in body weight and the 2-h postglucose insulin level in metabolic syndrome patients, along with an increase in insulin resistance. 165 These findings suggested the potential of nootkatone to serve as a natural antiobesity product.…”