Oral Presentation The Annual Scientific Meeting of the Australian Diabetes Society and the Australian Diabetes Educators Association 2013

Fructose Diet-Induced ER Stress Involves Suppressed Autophagy via the mTOR Signalling Pathway (#177)

Hao Wang 1 , Ruoqiong Sun 1 , Xiao-Yi Zeng 1 , Stanley Chan 1 , Juan C Molero 1 , Jiming Ye 1
  1. Molecular Pharmacology for Diabetes, Health Innovations Research Institute and School of Health Sciences, RMIT University, Melbourne, VIC, Australia

Excess consumption of high carbohydrate (mainly due to fructose) is an important contributor of hepatic steatosis and insulin resistance in humans. High fructose (HFru) diet is known to induce hepatic steatosis and insulin resistance by excess de novo lipogenesis which has recently been attributed to endoplasmic reticulum (ER) stress. As inhibition of autophagy has been reported to cause ER stress, the present study investigated whether HFru diet may induce hepatic ER stress by altering autophagy in mice with two-week HFru feeding. The results showed that HFru feeding impaired glucose tolerance and insulin signalling in the liver along with hepatic steatosis. As expected, ER stress was induced by HFru feeding as indicated by increases in phosphorylation of IRE1 (5 fold) and spliced XBP1 (3 fold, both p<0.01). Interestingly, along with these changes, the key proteins for autophagy, Atg7 and LC3-II, were significantly reduced (25% and 30% respectively) while p62 was increased by 30% (all p<0.01), suggesting an inhibition of autophagy in the liver by HFru feeding. As mTOR has been reported to inhibit autophagy, we then investigated if the observed suppression of autophagy may be due to the activation of the mTOR pathway. We found significant increases in the phosphorylation of mTOR (67%) and its downstream targets p70 S6K (2 fold) and 4E-BP1 (25%, all p<0.05). Hepatic ER stress was detected as early as 2 hours of HFru feeding in fasted mice when autophagy was suppressed in association with the activation of the mTOR pathway. Our results indicate that the mTOR-autophagy pathway may be an important mechanism for HFru-induced hepatic ER stress which may lead to subsequent development of insulin resistance and glucose intolerance. These findings may reveal potential new avenues for the treatment of insulin resistance by targeting key steps of these pathways in the liver.