Role of S-adenosylmethionine in two experimental models of pancreatitis.
Severe necrotizing pancreatitis occurs in young female mice fed a choline-deficient and ethionine-supplemented (CDE) diet. Although the mechanism of the pancreatitis is unknown, one consequence of this diet is depletion of hepatic S-adenosylmethionine (SAM). SAM formation is catalyzed by methionine adenosyltransferases (MATs), which are encoded by liver-specific (MAT1A) and non-liver-specific (MAT2A) genes. In this work, we examined changes in pancreatic SAM homeostasis in mice receiving the CDE diet and the effect of SAM treatment. We found that both MAT forms are expressed in normal pancreas and pancreatic acini. After 48 h of the CDE diet, SAM levels decreased 50% and MAT1A-encoded protein disappeared via post-translational mechanisms, whereas MAT2A-encoded protein increased via pretranslational mechanisms. CDE-fed mice exhibited extensive necrosis, edema, and acute pancreatic inflammatory infiltration, which were prevented by SAM treatment. However, old female mice consuming the CDE diet that do not develop pancreatitis showed a similar fall in pancreatic SAM level. SAM was also protective in cerulein-induced pancreatitis in the rat, but the protection was limited. Although the pancreatic SAM level fell by more than 80% in the MAT1A knockout mice, no pancreatitis developed. This study thus provides several novel findings. First, the so-called liver-specific MAT1A is highly expressed in the normal pancreas and pancreatic acini. Second, the CDE diet causes dramatic changes in the expression of MAT isozymes by different mechanisms. Third, in contrast to the situation in the liver, where absence of MAT1A and decreased hepatic SAM level can lead to spontaneous tissue injury, in the pancreas the roles of SAM and MAT1A appear more complex and remain to be defined.
Lu
Shelly C
SC
Division of Gastroenterology and Liver Diseases, USC Liver Disease Research Center, Keck School of Medicine USC, Los Angeles, California 90033, USA. shellylu@hsc.usc.edu
Gukovsky
Ilya
I
Lugea
Aurelia
A
Reyes
Christopher N
CN
Huang
Zong-Zhi
ZZ
Chen
Lixin
L
Mato
José M
JM
Bottiglieri
Teodoro
T
Pandol
Stephen J
SJ
D000284:Administration, Oral; D000818:Animals; D002108:Ceruletide; D002796:Choline Deficiency / Q000150:complications; D005001:Ethionine / Q000008:administration & dosage; D005260:Female; D008716:Methionine Adenosyltransferase / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D010179:Pancreas / Q000201:enzymology / Q000473:pathology; D010195:Pancreatitis / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control; D012436:S-Adenosylmethionine / Q000008:administration & dosage / Q000502:physiology*
D012436:S-Adenosylmethionine; D002108:Ceruletide; D008716:Methionine Adenosyltransferase; D005001:Ethionine