Cordycepin Ameliorates Nonalcoholic Steatohepatitis by Activation of the AMP‐Activated Protein Kinase Signaling Pathway

Abstract

BaCKgRoUND aND aIMS: Nonalcoholic fatty liver disease, especially nonalcoholic steatohepatitis (NASH), has become a major cause of liver transplantation and liverassociated death. NASH is the hepatic manifestation of metabolic syndrome and is characterized by hepatic steatosis, inflammation, hepatocellular injury, and different degrees of fibrosis. However, there is no US Food and Drug Administration-approved medication to treat this devastating disease. Therapeutic activators of the AMP-activated protein kinase (AMPK) have been proposed as a potential treatment for metabolic diseases such as NASH. Cordycepin, a natural product isolated from the traditional Chinese medicine Cordyceps militaris, has recently emerged as a promising drug candidate for metabolic diseases. appRoaCH aND ReSUltS: We evaluated the effects of cordycepin on lipid storage in hepatocytes, inflammation, and fibrosis development in mice with NASH. Cordycepin attenuated lipid accumulation, inflammation, and lipotoxicity in hepatocytes subjected to metabolic stress. In addition, cordycepin treatment significantly and dose-dependently decreased the elevated levels of serum aminotransferases in mice with diet-induced NASH. Furthermore, cordycepin treatment significantly reduced hepatic triglyceride accumulation, inflammatory cell infiltration, and hepatic fibrosis in mice. In vitro and in vivo mechanistic studies revealed that a key mechanism linking the protective effects of cordycepin were AMPK phosphorylation-dependent, as indicated by the finding that treatment with the AMPK inhibitor Compound C abrogated cordycepin-induced hepatoprotection in hepatocytes and mice with NASH. CoNClUSIoN:Cordycepin exerts significant protective effects against hepatic steatosis, inflammation, liver injury, and fibrosis in mice under metabolic stress through activation of the AMPK signaling pathway. Cordycepin might be an AMPK activator that can be used for the treatment of NASH.

Micronized Palmitoylethanolamide Ameliorates Methionine- and Choline-Deficient Diet–Induced Nonalcoholic Steatohepatitis via Inhibiting Inflammation and Restoring Autophagy

“…AMPK is a key regulator that controls energy homeostasis. Previous studies have indicated that AMPK activation could prevent the progress of NASH (Hu et al, 2021;Lan et al, 2021). Our data have shown that PEA significantly enhanced AMPK phosphorylation, suggesting that AMPK may be the center regulator of lipid metabolism in the current study.…”

Instant Dark Tea Alleviates Hyperlipidaemia in High-Fat Diet-Fed Rat: From Molecular Evidence to Redox Balance and Beyond

“…Hepatic lipid metabolism is crucial for the controlling of the lipid homeostasis in whole body. Lipid metabolism is a complex process involved in the regulation of some crucial nuclear factors, such as fatty acid-binding proteins (FABPs), peroxisome proliferator-activated receptor γ (PPARγ ), CD36, and SCD1 (7). FABPs modulate lipid fluxes, trafficking, signaling, and metabolism (8).…”

Cordycepin augments the chemosensitivity of osteosarcoma to cisplatin by activating AMPK and suppressing the AKT signaling pathway

“…It has been reported that cordycepin may inhibit intracellular lipid accumulation through activation of AMPK via interaction with the γ1 subunit and might act as a novel AMPK activator for the treatment of hepatic steatosis, inflammation, liver injury, and a variety of tumors by activating the AMPK signaling pathway [ 12 , 16 , 17 ]. To determine whether cordycepin inhibits osteosarcoma cell growth through the AMPK pathway, we performed western blotting and found that the expression of p-AMPK was upregulated after treatment with cordycepin for 48 h. We also found that activation of AMPK was enhanced in the group treated with the combination of cordycepin and cisplatin compared to the group treated with cordycepin or cisplatin alone (Fig.…”

“…Cordycepin has been comfirm to inhibit drug-resistance non-small cell lung cancer progression through activating AMPK signaling pathway [ 26 ]. Cordycepin might be a novel AMPK activator that binds the α1 and γ1 subunits near the autoinhibitory domain of AMPK [ 17 , 27 ]. Our study revealed that cordycepin mediated an increase in AMPK phosphorylation, thereby inhibiting the proliferation of osteosarcoma cells and that the expression of phosphorylated AMPK increased more significantly when cordycepin was used in combination with cisplatin than when it was administered alone.…”