| Grp78 heterozygosity regulates chaperone balance in exocrine pancreas with differential response to cerulein-induced acute pancreatitis. | |
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MedLine Citation:
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PMID: 20971738 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The endoplasmic reticulum (ER) is abundant in the acinar cells of the exocrine pancreas. To test the role of ER homeostasis in acute pancreatitis, we manipulated GRP78 levels, a major ER chaperone, in mice. Grp78(+/+) and (+/-) littermates were fed either a regular diet (RD) or a high-fat diet. Acinar cells were examined for ER structure by electron microscopy, and ER chaperone levels were assessed by immunoblotting. Pancreatitis was induced by cerulein injection, and multiple pathological parameters were analyzed. Grp78(+/-) mice showed decreased GRP78 expression in acinar cells. Exocrine pancreata of RD-fed Grp78(+/-) mice in an outbred C57BL/6 × 129/sv genetic background exhibited ER lumen dilation, a reduction in chaperones calnexin (CNX) and calreticulin (CRT), and exacerbated pancreatitis associated with high CHOP induction. With the high-fat diet regimen, Grp78 heterozygosity triggered GRP94 up-regulation and restoration of GRP78, CNX, and CRT to wild-type levels, corresponding with mitigated pancreatitis on cerulein insult. Interestingly, after backcrossing into the C57BL/6 background, RD-fed Grp78(+/-) mice exhibited an increase in GRP94 and levels of CNX and CRT equivalent to wild type, associated with decreased experimental pancreatitis severity. Administration of a chemical chaperone, 4-phenolbutyrate, was protective against cerulein-induced death. Thus, in exocrine pancreata, Grp78 heterozygosity regulates ER chaperone balance, in dietary- and genetic background-dependent manners, and improved ER protein folding capacity might be protective against pancreatitis. |
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Authors:
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Risheng Ye; Olga A Mareninova; Ernesto Barron; Miao Wang; David R Hinton; Stephen J Pandol; Amy S Lee |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. Date: 2010-10-22 |
Journal Detail:
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Title: The American journal of pathology Volume: 177 ISSN: 1525-2191 ISO Abbreviation: Am. J. Pathol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-01 Completed Date: 2011-03-15 Revised Date: 2011-12-21 |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: United States |
Other Details:
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Languages: eng Pagination: 2827-36 Citation Subset: AIM; IM |
Affiliation:
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Department of Biochemistry and Molecular Biology, University of Southern California Keck School of Medicine, USC Norris Comprehensive Cancer Center, 1441 Eastlake Avenue, Los Angeles, CA 90089-9176, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acute Disease Animals Caerulein* Dietary Fats / pharmacology Endoplasmic Reticulum / drug effects, metabolism Gastrointestinal Agents Heat-Shock Proteins / genetics*, physiology Heterozygote Mice Mice, Inbred C57BL Mice, Transgenic Molecular Chaperones / metabolism* Pancreas, Exocrine / drug effects, metabolism* Pancreatitis / genetics*, metabolism Stress, Physiological / drug effects, genetics Unfolded Protein Response / drug effects, genetics, physiology |
| Grant Support | |
ID/Acronym/Agency:
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AA11999/AA/NIAAA NIH HHS; AA16010/AA/NIAAA NIH HHS; CA027607/CA/NCI NIH HHS; DK048522/DK/NIDDK NIH HHS; DK070582/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Dietary Fats; 0/Gastrointestinal Agents; 0/Heat-Shock Proteins; 0/Molecular Chaperones; 0/molecular chaperone GRP78; 17650-98-5/Caerulein |
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