title: Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis.
abstract: Although ethanol causes acute pancreatitis (AP) and lipolytic fatty acid (FA) generation worsens AP, the contribution of ethanol metabolites of FAs, ie, FA ethyl esters (FAEEs), to AP outcomes is unclear. Previously, pancreata of dying alcoholics and pancreatic necrosis in severe AP, respectively, showed high FAEEs and FAs, with oleic acid (OA) and its ethyl esters being the most abundant. We thus compared the toxicities of FAEEs and their parent FAs in severe AP. Pancreatic acini and peripheral blood mononuclear cells were exposed to FAs or FAEEs in vitro. The triglyceride of OA (i.e., glyceryl tri-oleate) or OAEE was injected into the pancreatic ducts of rats, and local and systemic severities were studied. Unsaturated FAs at equimolar concentrations to FAEEs induced a larger increase in cytosolic calcium, mitochondrial depolarization, and necro-apoptotic cell death. Glyceryl tri-oleate but not OAEE resulted in 70% mortality with increased serum OA, a severe inflammatory response, worse pancreatic necrosis, and multisystem organ failure. Our data show that FAs are more likely to worsen AP than FAEEs. Our observations correlate well with the high pancreatic FAEE concentrations in alcoholics without pancreatitis and high FA concentrations in pancreatic necrosis. Thus, conversion of FAs to FAEE may ameliorate AP in alcoholics.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Krutika
authors.initials: K
authors.lastname: Patel
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
authors.forename: Chandra
authors.initials: C
authors.lastname: Durgampudi
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Pawan
authors.initials: P
authors.lastname: Noel
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Ram N
authors.initials: RN
authors.lastname: Trivedi
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Cristiane
authors.initials: C
authors.lastname: de Oliveira
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Scottsdale, Arizona. Electronic address: singh.vijay@mayo.edu.
authors.forename: Vijay P
authors.initials: VP
authors.lastname: Singh
mesh_terms: D000208:Acute Disease; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004195:Disease Models, Animal; D004952:Esters / Q000633:toxicity*; D000431:Ethanol / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism* / Q000633:toxicity*; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D010179:Pancreas / Q000378:metabolism*; D010195:Pancreatitis / Q000378:metabolism*; D017208:Rats, Wistar
chemical_list: D004952:Esters; D005227:Fatty Acids; D000431:Ethanol; D002118:Calcium