Grp78 Heterozygosity Regulates Chaperone Balance in Exocrine Pancreas with Differential Response to Cerulein-Induced Acute Pancreatitis

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 x 129/sv genetic background exhibited ER lumen dilation a reduction m 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 ex perimental 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 (Am J Pathol 2010 177 2827-2836, DOI 10 2353/ajpath 2010 100368)