Atractylenolide III ameliorates Non-Alcoholic Fatty Liver Disease by activating Hepatic Adiponectin Receptor 1-Mediated AMPK Pathway

Abstract

Background: Nonalcoholic fatty liver disease (NAFLD) is the most frequent cause of chronic liver diseases worldwide. At present, there are no effective pharmacological therapies for NAFLD except lifestyle intervention-mediated weight loss. Atractylenolide III (ATL III), the major bioactive component found in Atractylode smacrocephala Koidz, has been shown to exert anti-oxidant, anti-tumor, anti-allergic response, anti-bacterial effects and cognitive protection. Here we investigate the therapeutic potential and underlying mechanisms of ATL III for the treatment of NAFLD. Methods: Male C57BL/6J mice were fed a high-fat diet (HFD) and treated with ATL III. Lipid accumulation was analyzed by Oil Red O staining in liver tissues and free fatty acids (FFAs)-treated hepatocytes. AMP-activated protein (AMPK) and sirtuin 1(SIRT1) signaling pathways were inhibited by Compound C and EX527 in vitro, respectively. Small-interfering RNA (siRNA) was used to knockdown adiponectin receptor 1 (AdipoR1) expression in HepG2 cells. Results: ATL III treatment ameliorated liver injury and hepatic lipid accumulation in the HFD-induced NAFLD mouse model as demonstrated by that ATL III administration significantly reduced serum levels of alanine aminotransferase, glutamic oxaloacetic transaminase, triglycerides, total cholesterol and low-density lipoprotein. Furthermore, treatment with ATL III alleviated hepatic oxidative stress, inflammation and fibrosis in the HFD feeding model. To study the underlying mechanisms, we performed Computer Aided Design assay and found that open-formed AdipoR1 and adiponectin receptor 2 were the potential receptors targeted by ATL III. Interestingly, HFD feeding or FFAs treatment only reduced hepatic AdipoR1 expression, while such reduction was abolished by ATL III administration. In addition, in vitro treatment with ATL III activated the AdipoR1 downstream AMPK /SIRT1 signaling pathway and reduced lipid deposition in HepG2 cells, which was diminished by silencing AdipoR1. Finally, inhibition of AMPK or SIRT1, the AdipoR1 downstream signaling, abolished the protective effects of ATL III on lipid deposition and oxidative stress in FFAs-treated HepG2 cells. Conclusion: Our findings suggest that ATL III is a therapeutic drug for the treatment of NAFLD and such protective effect is mediated by activating hepatic AdipoR1-mediated AMPK/SIRT1 signaling pathway.

Lactobacillus plantarum ZJUIDS14 alleviates non-alcoholic fatty liver disease in mice in association with modulation in the gut microbiota

“…Treatment with L. plantarum ZJUIDS14 induced a marked decrease in OGTT and ITT AUC values. Consistent with other studies (27)(28)(29), HFD significantly increased the levels of plasma TG, FFA, TC, and LDL-C. Moreover, the plasma levels of HDL-C were increased and TG, FFA, and LDL-C were distinctly reduced * P < 0.05, * * P < 0.01, * * * P < 0.001 vs NFD group; # P < 0.05, ## P < 0.01 vs HFD group.…”

The AMPK pathway in fatty liver disease

“…Besides, it can inhibit the secretion of gluconeogenesis-related enzymes and glucagon-like peptide 1 (GLP-1) as well as glucagon signaling by delaying the absorption of glucose in the gastrointestinal tract ( Sunny et al, 2017 ). In an in vivo and in vitro experiment, Li et al (2022) found, by combining computer-aided design analysis, that Atractylenolide III could reduce lipid accumulation by upregulating liver adiponectin receptor 1, activating AMPK pathway, improving the phosphorylation of LKB1 and AMPK, and promoting the expression of fatty acid oxidation proteins CPT1A and PGC1α; At the same time, it could upregulate the activities of antioxidant proteins Sirt3 and Nrf2, inhibit oxidative stress response, and ultimately improve NAFLD ( Li et al, 2022 ). In the in vitro experiment of hepatocytes exposed to ethanol, dihydroquercetin was found to significantly increase the activity and phosphorylation of LKB1 and AMPK to inhibit the expression of ACC and SREBP-1c, thereby inhibiting lipid production, promoting fatty acid oxidation and finally reducing fat accumulation ( Zhang et al, 2018 ).…”

Non-Alcoholic Fatty Liver Disease (NAFLD) Pathogenesis and Natural Products for Prevention and Treatment

“…Atractylenolide III is the major bioactive component found in Atractylodes macrocephala Koidz. The study showed that Atractylenolide III ameliorated liver injury and liver lipid accumulation in HFD-induced NAFLD mouse models by activating the AMPK/SIRT1 pathway [ 119 ]. Salvianolic acid A is a natural polyphenol compound extracted from Salvia miltiorrhiza Bunge (known as Danshen in China).…”

“…Antrodan High-fat diet (HFD)-fed mouse [49] (2) Emodin Egg yolk powder-fed Zebrafish [88] (3) Four flavonoids extracted from Lomatogonium rotatum High fructose-fed rats [89] (4) Oxyresveratrol HFD-fed mouse, liver X receptor α (LXRα) stimulated HepG2, Hep3B and Huh-7 cells [90] (5) Cynandione A LXRα stimulated HepG2 cells [91] (6) Gomisin N HFD-fed mouse, LXRα or palmitic acid (PA) stimulated HepG2 cells [92] (7) Tomatidine HFD-fed mouse, Oleic acid (OA) stimulated FL83B [93] (8) Licochalcone A HFD-fed mouse, OA stimulated HepG2 cells [94] Alleviating oxidative stress (9) Hesperetin HFD-fed rat, OA stimulated HepG2 cells [99] (10) Gastrodin HFD-fed mouse, high-fat and high-carbohydrate diet (HFHC)-fed rat, OA stimulated HL-7702 cells [ Alleviating endoplasmic reticulum stress (16) Aucubin HFD-fed rat, PA stimulated HepG2 cells [112] (17) Geniposide HFD-fed rat, PA stimulated HepG2 cells [112] (18) Tanshinone IIA PA stimulated HepG2 cells [114] Alleviating inflammatory reaction (19) Resveratrol HFD-fed mouse [116] (20) Atractylenolide III HFD-fed mouse, OA plus PA stimulated HepG2 cells [119] (21) Salvianolic acid A HFHC-fed mouse, PA stimulated HepG2 cells [120] (22) Silibinin MCD-fed mouse, OA plus PA stimulated mouse NCTC-1469 cells [121] (23) Honokiol MCD-fed mouse, OA plus PA stimulated mouse NCTC-1469 cells [122] (24) Ursolic acid HFD-fed mouse [123] (25) Hairy calycosin HFD-fed rat [124] Silibinin is a flavonolignan isolated from the fruit and seeds of Milk thistle (Silybum marianum (L.) Gaertn.). Silibinin prevents NASH by modulating the JNK pathway.…”