The role of ER stress in lipogenesis and insulin resistance in response to over nutrition

Insulin resistance is one of the major defect of type 2 diabetes. Excess lipid and endoplasmic reticulum (ER) stress have been suggested to induce hepatic insulin resistance. However, the mechanisms of the development of insulin resistance relating to excess lipid or ER stress remain unclear.<br><br>The aims of the thesis were to investigate: 1) the role of ER stress in lipogensis and development of hepatic insulin resistance and, 2) the relationship between ER stress and lipogenesis.<br><br>The first study was to determine the contribution of ER stress and excess lipid on the onset of hepatic insulin resistance in high fructose (HFru)-fed mice. After feeding with HFru for one day, IRE1/XBP1 branch of the ER stress was activated. Simultaneously, lipogenic enzymes, transcription factor and triglyceride content in the liver increased. Insulin-stimulated phosphorylated Akt was suppressed. Blocking IRE1 activity by TUDCA abolished fructose-dependent increases in JNK activity and IRS serine phosphorylation, and improved Akt phosphorylation without altering hepatic steatosis or PKCϵ. The second study was to interrogate the role of excess lipid or JNK in hepatic insulin resistance in HFru-fed mice. Mice were fed with HFru for 2 weeks. Fenofibrate (FB), a PPARα agonist, was administrated to reduce lipid accumulation. FB treatment eliminated glucose intolerance, hepatic steatosis and insulin signaling transduction. Both IRE1/XBP1 and PEKR/eIF2α branches of ER stress were activated. FB administration increased fatty acid oxidation and reduced diacyglycerols levels. The results from these HFru studies suggested that: 1) ER stress and lipogenesis both contribute to HFru-induced hepatic insulin resistance; 2) activation of JNK rather than lipid accumulation is a key early trigger of ER stress related hepatic insulin resistance induced by HFru feeding and; 3) lipid accumulation, rather than JNK or IKK activation, is pivotal for ER stress to cause hepatic insulin resistance when the mice were challenged with HFru diet for a long time.<br><br>To further explore the interaction between ER stress and lipogenesis, fructose was used to induce ER stress in cultured cells. Betulin was applied to cells treated with fructose. Lipogenic enzymes were significantly diminished by betulin. The magnified fructose-induced phosphorylation of IRE1 and eIF2α was not altered, suggesting that increasing lipogenesis does not contribute to the activation of IRE1 and PERK branches in context of fructose.<br><br>In another study, mice were fed with a high fat (HFat) diet for one day or 2 weeks. Hepatic diacyglycerols were increased in HFat-fed mice. Interestingly, HFat-fed mice did not show activated ER stress. These results indicated that hepatic insulin resistance was induced via different mechanisms in the face of fatty acid influx. These observations also suggested that ER stress is unlikely to result from excess lipid.<br><br>In summary, ER stress might be more critical at early stage of insulin resistance in the context of HFru feeding and this fructose-induced ER stress is independent of excess lipid. Accordingly, the predominantly negative effect of JNK activation induced by ER stress might be overcome by the persistently increasing lipid accumulation, possibly becomes a secondary inducer of insulin resistance in long term.