title: Acute lipotoxicity regulates severity of biliary acute pancreatitis without affecting its initiation.
abstract: Obese patients have worse outcomes during acute pancreatitis (AP). Previous animal models of AP have found worse outcomes in obese rodents who may have a baseline proinflammatory state. Our aim was to study the role of acute lipolytic generation of fatty acids on local severity and systemic complications of AP. Human postpancreatitis necrotic collections were analyzed for unsaturated fatty acids (UFAs) and saturated fatty acids. A model of biliary AP was designed to replicate the human variables by intraductal injection of the triglyceride glyceryl trilinoleate alone or with the chemically distinct lipase inhibitors orlistat or cetilistat. Parameters of AP etiology and outcomes of local and systemic severity were measured. Patients with postpancreatitis necrotic collections were obese, and 13 of 15 had biliary AP. Postpancreatitis necrotic collections were enriched in UFAs. Intraductal glyceryl trilinoleate with or without the lipase inhibitors resulted in oil red O-positive areas, resembling intrapancreatic fat. Both lipase inhibitors reduced the glyceryl trilinoleate-induced increase in serum lipase, UFAs, pancreatic necrosis, serum inflammatory markers, systemic injury, and mortality but not serum alanine aminotransferase, bilirubin, or amylase. We conclude that UFAs are enriched in human necrotic collections and acute UFA generation via lipolysis worsens pancreatic necrosis, systemic inflammation, and injury associated with severe AP. Inhibition of lipolysis reduces UFA generation and improves these outcomes of AP without interfering with its induction.
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center Pasavant, Pittsburgh, Pennsylvania.
authors.forename: Chandra
authors.initials: C
authors.lastname: Durgampudi
authors.affiliation: Department of Medicine, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Pawan
authors.initials: P
authors.lastname: Noel
authors.affiliation: Department of Medicine, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Krutika
authors.initials: K
authors.lastname: Patel
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Rachel
authors.initials: R
authors.lastname: Cline
authors.affiliation: Department of Medicine, Mayo Clinic, Scottsdale, Arizona.
authors.forename: Ram N
authors.initials: RN
authors.lastname: Trivedi
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: James P
authors.initials: JP
authors.lastname: DeLany
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Dhiraj
authors.initials: D
authors.lastname: Yadav
authors.affiliation: Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Georgios I
authors.initials: GI
authors.lastname: Papachristou
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center Pasavant, Pittsburgh, Pennsylvania.
authors.forename: Chathur
authors.initials: C
authors.lastname: Acharya
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center Pasavant, Pittsburgh, Pennsylvania.
authors.forename: Deepthi
authors.initials: D
authors.lastname: Jaligama
authors.affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Sarah
authors.initials: S
authors.lastname: Navina
authors.affiliation: Department of Medicine, Washington University, St. Louis, Missouri.
authors.forename: Faris
authors.initials: F
authors.lastname: Murad
authors.affiliation: 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: D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D005260:Female; D006801:Humans; D008049:Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism; D008066:Lipolysis; D008297:Male; D019283:Pancreatitis, Acute Necrotizing / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012720:Severity of Illness Index
chemical_list: D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D008049:Lipase