title: The role of fat and alcohol in acute pancreatitis: A dangerous liaison.
abstract: Excessive alcohol consumption is a major trigger for severe acute pancreatitis which may lead to multi-organ dysfunction and premature death of the individual. Hyperlipidaemia is a risk factor for both acute and chronic pancreatitis and the role of fatty acids in mediating damage has received increasing attention in recent years. In the pancreas ethanol is metabolised by both oxidative and non-oxidative pathways. The latter, predominant route generates fatty acid ethyl esters (FAEEs) from fatty acid substrates via the action of diverse enzymes called FAEE synthases, including carboxylester lipase an enzyme synthesized and secreted by the acinar cells. Inhibition of the oxidative pathway promotes formation of FAEEs which induce sustained elevations of cytosolic calcium leading to inhibition of mitochondrial function, loss of ATP and necrosis of isolated pancreatic acinar cells. Furthermore, FAEEs undergo hydrolysis in the mitochondria releasing free fatty acids that exert toxic effects. Our recent work has shown that pharmacological inhibition of carboxylester lipase ameliorated detrimental effects of non-oxidative ethanol metabolism in isolated pancreatic acinar cells in vitro and in a new in vivo experimental model of alcoholic acute pancreatitis, revealing a specific enzyme target for ethanol-induced injury. Strategies that prevent FAEE synthesis, protect mitochondria, reduce calcium overload or sustain calcium homeostasis by ATP provision may provide promising therapeutic avenues for the treatment of alcoholic acute pancreatitis.
authors.affiliation: Department of Cellular & Molecular Physiology & NIHR Liverpool Pancreas Biomedical Research Unit, RLBUHT, Institute of Translational Medicine, University of Liverpool, UK. Electronic address: criddle@liv.ac.uk.
authors.forename: David N
authors.initials: DN
authors.lastname: Criddle
mesh_terms: D000208:Acute Disease; D000437:Alcoholism / Q000150:complications* / Q000378:metabolism; D000818:Animals; D005227:Fatty Acids / Q000378:metabolism*; D006801:Humans; D028361:Mitochondrial Diseases / Q000209:etiology / Q000378:metabolism; D019512:Pancreatitis, Alcoholic / Q000209:etiology* / Q000378:metabolism
chemical_list: D005227:Fatty Acids
keywords: Acute pancreatitis; Alcohol; Calcium overload; Carboxylester lipase; Fatty acid ethyl esters; Mitochondrial dysfunction