title: Lipolysis of visceral adipocyte triglyceride by pancreatic lipases converts mild acute pancreatitis to severe pancreatitis independent of necrosis and inflammation.
abstract: Visceral fat necrosis has been associated with severe acute pancreatitis (SAP) for over 100 years; however, its pathogenesis and role in SAP outcomes are poorly understood. Based on recent work suggesting that pancreatic fat lipolysis plays an important role in SAP, we evaluated the role of pancreatic lipases in SAP-associated visceral fat necrosis, the inflammatory response, local injury, and outcomes of acute pancreatitis (AP). For this, cerulein pancreatitis was induced in lean and obese mice, alone or with the lipase inhibitor orlistat and parameters of AP induction (serum amylase and lipase), fat necrosis, pancreatic necrosis, and multisystem organ failure, and inflammatory response were assessed. Pancreatic lipases were measured in fat necrosis and were overexpressed in 3T3-L1 cells. We noted obesity to convert mild cerulein AP to SAP with greater cytokines, unsaturated fatty acids (UFAs), and multisystem organ failure, and 100% mortality without affecting AP induction or pancreatic necrosis. Increased pancreatic lipase amounts and activity were noted in the extensive visceral fat necrosis of dying obese mice. Lipase inhibition reduced fat necrosis, UFAs, organ failure, and mortality but not the parameters of AP induction. Pancreatic lipase expression increased lipolysis in 3T3-L1 cells. We conclude that UFAs generated via lipolysis of visceral fat by pancreatic lipases convert mild AP to SAP independent of pancreatic necrosis and the inflammatory response.
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania; Mayo Clinic, Scottsdale, Arizona.
authors.forename: Krutika
authors.initials: K
authors.lastname: Patel
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania; Mayo Clinic, Scottsdale, Arizona.
authors.forename: Ram N
authors.initials: RN
authors.lastname: Trivedi
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Chandra
authors.initials: C
authors.lastname: Durgampudi
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania; Mayo Clinic, Scottsdale, Arizona.
authors.forename: Pawan
authors.initials: P
authors.lastname: Noel
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Cline
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: James P
authors.initials: JP
authors.lastname: DeLany
authors.affiliation: Department of Pathology, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Sarah
authors.initials: S
authors.lastname: Navina
authors.affiliation: Department of Medicine, University of Pittsburgh Medical Center and the University of Pittsburgh, Pittsburgh, Pennsylvania; Mayo Clinic, Scottsdale, Arizona. Electronic address: singh.vijay@mayo.edu.
authors.forename: Vijay P
authors.initials: VP
authors.lastname: Singh
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002108:Ceruletide; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007783:Lactones / Q000494:pharmacology; D008049:Lipase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008066:Lipolysis / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D008820:Mice, Obese; D009336:Necrosis / Q000378:metabolism / Q000473:pathology; D000077403:Orlistat; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D007783:Lactones; D014280:Triglycerides; D002108:Ceruletide; D000077403:Orlistat; D008049:Lipase