Hepatic alcohol dehydrogenase deficiency induces pancreatic injury in chronic ethanol feeding model of deer mice
| Autor: | Vsevolod L. Popov, Inas H. El-Mehallawi, Magdy M. Ashmawy, Samir M. Amer, G. A. Shakeel Ansari, Bhupendra S. Kaphalia, Bill A. Rampy, Ramu Kakumanu, Kamlesh K. Bhopale |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Glucose-regulated protein Clinical Biochemistry Endoplasmic Reticulum Cathepsin B Article Pathology and Forensic Medicine 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Peromyscus Internal medicine medicine Animals Inositol Molecular Biology Pancreas Alcohol dehydrogenase biology Ethanol ATF6 Fatty Acids Alcohol Dehydrogenase medicine.disease Endoplasmic Reticulum Stress Alcoholism Disease Models Animal Ethyl Ethers 030104 developmental biology medicine.anatomical_structure Endocrinology chemistry Liver biology.protein Unfolded protein response Pancreatitis 030211 gastroenterology & hepatology Blood Alcohol Content |
| Popis: | The single most common cause of chronic pancreatitis (CP, a serious inflammatory disease) is chronic alcohol abuse, which impairs hepatic alcohol dehydrogenase (ADH, a major ethanol oxidizing enzyme). Previously, we found ~5 fold greater fatty acid ethyl esters (FAEEs), and injury in the pancreas of hepatic ADH deficient (ADH-) vs. hepatic normal ADH (ADH+) deer mice fed 3.5g% ethanol via liquid diet daily for two months. Therefore, progression of ethanol-induced pancreatic injury was determined in ADH- deer mice fed ethanol for four months to delineate the mechanism and metabolic basis of alcoholic chronic pancreatitis (ACP). In addition to a substantially increased blood alcohol concentration and plasma FAEEs, significant degenerative changes, including atrophy and loss of acinar cells in some areas, ultrastructural changes evident by such features as swelling and disintegration of endoplasmic reticulum (ER) cisternae and ER stress were observed in the pancreas of ethanol-fed ADH- deer mice vs. ADH+ deer mice. These changes are consistent with noted increases in pancreatic injury markers (plasma lipase, pancreatic trypsinogen activation peptide, FAEE synthase and cathepsin B) in ethanol-fed ADH- deer mice. Most importantly, an increased levels of pancreatic glucose regulated protein (GRP) 78 (a prominent ER stress marker) were found to be closely associated with increased phosphorylated eukaryotic initiation factor (eIF) 2α signaling molecule in PKR-like ER kinase branch of unfolded protein response (UPR) as compared to X box binding protein 1S and activating transcription factor (ATF)6 - 50kDa protein of inositol requiring enzyme 1α and ATF6 branches of UPR, respectively, in ethanol-fed ADH- vs. ADH+ deer mice. These results along with findings on plasma FAEEs, and pancreatic histology and injury markers suggest a metabolic basis of ethanol-induced pancreatic injury, and provide new avenues to understand metabolic basis and molecular mechanism of ACP. |
| Databáze: | OpenAIRE |
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