Effects of the postprandial environment on the unfolded protein response
Date
2009
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Abstract
Background and specific aims. Newly synthesized proteins must undergo post-translational modifications such as folding and glycosylation to become fully functional. The lumen of the endoplasmic reticulum (ER) is a major site of protein folding and processing. The ER can respond to an increase in unfolded proteins (termed "ER stress") by activating the Unfolded Protein Response (UPR), a quality control mechanism which maintains ER homeostasis. Recent studies have demonstrated that the UPR is also involved in the regulation of a diverse array of cellular processes including glucose homeostasis, lipogenesis, and protein synthesis. The liver plays a central role in nutrient metabolism and maintaining glucose homeostasis. Further, in the postprandial state, both lipogenesis and protein synthesis are stimulated in the liver. However, the role of the UPR in the postprandial regulation of these processes has not been studied. Therefore, the first aim of the present study was to examine and characterize the regulation of the UPR in the postprandial state in the liver. One of the main rate limiting steps in protein synthesis is regulated by the mammalian target of rapamycin complex-I (mTORC I). Thus, the second aim of the current study was to examine the role of mTORC1 in the postprandial regulation of the UPR. Methods. Rats in Study 1 were fed a single starch or high sucrose meal and sacrificed either 1 or 7 hours post-feeding period. Plasma glucose and insulin were measured and hepatic tissue was examined for markers of UPR activation. Rats in Study 2 were injected with rapamycin, an inhibitor of mTORC1, prior to meal feeding. Rats were sacrificed 1 or 7 hours post-feeding period and blood and liver tissue were collected for analysis. To examine the role of insulin and glucose in the postprandial activation of the UPR H4IIE liver cells were exposed to varying amounts of glucose and insulin in the presence or absence of rapamycin. Results. Feeding activated select components of the UPR, including spliced X-box binding protein-1 (XBP1) and increased GRP78 and GRP94 mRNA expression. Rapamycin inhibited the postprandial increase of these components. The phosphorylation of eif2-α protein was not increased postprandially in the liver. Data from H4IIE cells demonstrate that insulin in the presence of glucose can activate UPR components in an mTORC1 dependent manner. Conclusion. The current study demonstrates that select components of the UPR are activated in the liver in the postprandial state. This activation appears to be insulin and mTORC1 dependent.
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Subject
ER stress
postprandial
unfolded protein response
nutrition