The role of endoplasmic reticulum proteins GRP78 and IP3R1 in regulation of glucose homeostasis and acute pancreatitis

The endoplasmic reticulum (ER) is an intracellular organelle for protein folding, lipid synthesis and Ca2+ storage. It also is responsible for transporting most secreted and transmembrane proteins to their proper cellular locations. ER undergoes stress when the protein load exceeds its folding capacity, and cellular signaling cascades are activated as unfolded protein response (UPR). GRP78 is a major chaperone assisting protein folding, as well as a master regulator of UPR signaling. In this thesis, we discovered that heterozygosity of Grp78 enhances energy expenditure through upregulation of mitochondria activity, and alleviate high fat diet (HFD)-induced obesity and type 2 diabetes in mouse. The latter is also achieved through increase in insulin sensitivity in the white adipose tissue (WAT) of HFD-fed Grp78+/- mice, with adaptive UPR improving ER folding capacity and quality control. This mechanism is validated through overexpression of the active form of ATF6, a transcription factor known to upregulate ER chaperones. This induces protective UPR and improves insulin signaling in mouse embryonic fibroblasts (MEFs) upon ER stress. In the exocrine pancreatic acinar cells, Grp78 heterozygosity differentially regulates ER chaperone levels in a diet- and genetic background-dependent manner. The modulation of chaperone balance correlates with the ER morphology as well as the severity of cerulein-induced acute pancreatitis. Administration of chemical chaperone 4-phenolbutyrate (4-PBA) protects pancreatic acinar cells from cerulein-induced death. We also uncovered a novel role of the ER Ca2+ channel IP3R1 in glucose homeostasis is also discovered in mouse models. Progressive glucose intolerance is serendipitously observed in one line of transgenic mouse model resulting from genomic integration of the transgene. Itpr1, the IP3R1-encoding gene, is among the 10 loci disrupted by the gene insertion. The Itpr1 heterozygous mutant mice, opt/+, develop early-onset glucose intolerance. The opt/+ mice are more susceptible to HFD-induced hyperglycemia, glucose intolerance and insulin resistance. In conclusion, the role of GRP78 in type 2 diabetes and acute pancreatitis is revealed as a modulator of UPR signaling and chaperone balance. IP3R1 is identified as a novel regulator of glucose metabolism in vivo and protects against diet-induced diabetes.