Endocrine Abstracts

Insulin has an important role in the regulation of hepatic metabolism during the nutritional transition from the fasted to the fed state. Insulin inhibits glucose production and activates hepatic glycogen synthesis and lipogenesis. The effect of insulin on the regulation of lipogenesis is mainly transcriptional. Lipogenic gene expression is controlled by SREBP-1c, a transcription factor which is synthetized as a precursor embedded in endoplasmic reticulum membranes and which requires proteolytic cleavage to be activated. Insulin stimulates both transcription and proteolytic cleavage of SREBP-1c. Paradoxically, in obese insulin resistant rodents, there is a loss of the inhibitory effects of insulin on gluconeogenesis whereas lipogenesis, an insulin dependent process, is maximally stimulated. An active lipogenesis in obese insulin resistant rodents suggests that SREBP-1c could be activated by a signal different from insulin. We develop here the idea that an endoplasmic reticulum (ER) stress could be this signal. We have analysed the effects of an activation/inhibition of ER stress on SREBP-1c and lipogenesis in in vitro and in vivo studies. An activation of the ER stress pathway stimulates SREBP-1c proteolytic cleavage and induces its lipogenic target genes in rat hepatocytes. In genetically obese mice, the hepatic ER stress pathway is activated. Selective inhibition of hepatic ER stress leads to a marked decrease in SREBP-1c processing and expression as well as in a decreased expression of lipogenic genes. In turn this reduces hepatic steatosis and serum triglycerides and restores insulin sensitivity with a concomitant reduction of blood glucose and plasma insulin. We conclude that the ER stress pathway has a major role in the development of hepatic steatosis in insulin resistant states by activating SREBP-1c and thus hepatic de novo lipogenesis. A pharmacological inhibition of the ER stress pathway could be a therapeutical way to reduce hepatic steatosis and improve glucose homeostasis.