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THE ROLE OF ENDOPLASMIC RETICULUM PROTEINS GRP78 AND IP3R1 IN
REGULATION OF GLUCOSE HOMEOSTASIS AND ACUTE PANCREATITIS
by
Risheng Ye
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(BIOCHEMISTRY AND MOLECULAR BIOLOGY)
December 2010
Copyright 2010 Risheng Ye
Object Description
| Title | The role of endoplasmic reticulum proteins GRP78 and IP3R1 in regulation of glucose homeostasis and acute pancreatitis |
| Author | Ye, Risheng |
| Author email | rishengy@usc.edu; rishengye@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Biochemistry & Molecular Biology |
| School | Keck School of Medicine |
| Date submitted | 2010 |
| Restricted until | Unrestricted |
| Date published | 2010-09-20 |
| Advisor (committee chair) | Lee, Amy S. |
| Advisor (committee member) |
Stallcup, Michael R. Dubeau, Louis |
| Abstract | 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. |
| Keyword | endoplasmic reticulum; GRP78; IP3R1; glucose homeostasis; diabetes; acute pancreatitis |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m3460 |
| Rights | Ye, Risheng |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Ye-4139 |
| Archival file | uscthesesreloadpub_Volume44/etd-Ye-4139.pdf |
Description
| Title | Page 1 |
| Full text | THE ROLE OF ENDOPLASMIC RETICULUM PROTEINS GRP78 AND IP3R1 IN REGULATION OF GLUCOSE HOMEOSTASIS AND ACUTE PANCREATITIS by Risheng Ye A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (BIOCHEMISTRY AND MOLECULAR BIOLOGY) December 2010 Copyright 2010 Risheng Ye |
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