Ascofuranone prevents ER stress-induced insulin resistance via activation of AMP-activated protein kinase in L6 myotube cells.
The current study presents that ascofuranone isolated from a phytopathogenic fungus, Ascochyta viciae, has antitumor activity against various transplantable tumors and a considerable hypolipidemic activity. AMP-activated protein kinase (AMPK) plays a critical role in cellular glucose and lipid homeostasis. We found that ascofuranone improves ER stress-induced insulin resistance by activating AMPK through the LKB1 pathway. In L6 myotube cells, ascofuranone treatment increased the phosphorylation of the Thr-172 residue of the AMPK alpha subunit and the Ser-79 subunit of acetyl-CoA carboxylase (ACC) and cellular glucose uptake. Ascofuranone-induced phosphorylation of AMPK and ACC was not increased in A549 cells lacking LKB1. Interestingly, ascofuranone treatment also improved insulin signaling impaired by ER stress in L6 myotube cells. These effects were all reversed by pretreatment with Compound C, an AMPK inhibitor or with adenoviral-mediated dominant-negative AMPK alpha 2. Taken together, these results indicated that ascofuranone-mediated enhancement of glucose uptake and reduction of impaired insulin sensitivity in L6 cells is predominantly accomplished by activating AMPK, thereby mediating beneficial effects in type 2 diabetes and insulin resistance.
Hwang
Seung-Lark
SL
Research Institute of Biomedical Engineering and Department of Pathology, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea.
Chang
Hyeun-Wook
HW
Lee
In-Kyu
IK
Yang
Byung-Keun
BK
Magae
Junji
J
Chang
Young-Chae
YC
D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000201:enzymology; D004789:Enzyme Activation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007329:Insulin Antagonists / Q000494:pharmacology*; D007333:Insulin Resistance; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D012717:Sesquiterpenes / Q000494:pharmacology*; D013312:Stress, Physiological
D000935:Antifungal Agents; D007328:Insulin; D007329:Insulin Antagonists; D012717:Sesquiterpenes; D055372:AMP-Activated Protein Kinases; C006640:ascofuranone; D005947:Glucose