Obesity related pancreatic fat worsens local injury via unsaturated fatty acids

Summary

Principal Investigator: VIJAY PREM SINGH
Abstract: DESCRIPTION (provided by applicant): Acute Pancreatitis is potentially lethal when severe and is increasing in incidence, resulting in significant health care burden and costs. Obesity is associated with severe AP. Mortality from AP after the first week results from severe pancreatic necrosis and its associated complications, allowing a therapeutic window period. However, care currently consists of conservative management and treatment of its complications. Severe pancreatic necrosis in humans occurs with fat necrosis, which results from the saponification of free fatty acids along with elevated adipokines. Whether these are an epiphenomenon or causal in the disease is unknown. PRELIMINARY DATA: To study this obesity-associated exacerbation of AP, we examined pancreas histology from autopsies of controls and patients with pancreatitis. We noted an increase in the amount of intrapancreatic fat (IPF) with BMI in both groups. In AP patients, there was significantly more fat necrosis compared with controls, which was accompanied by surrounding acinar necrosis, which decreased with increasing distance from the fat necrosis. This peri-fat acinar necrosis contributed to about half of the total acinar necrosis. In contrast, IPF in patients with chronic pancreatitis seemed unrelated to BMI, was accompanied by fibrosis, which walled off fat necrosis, limiting peri-fat acinar damage. To understand this mechanistically, we generated a novel acinar-adipocyte co-culture system. While acini and adipocytes functioned normally in this medium both individually and together in the presence of the lipase inhibitor orlistat, omission of orlistat resulted in near total acinar necrosis, as evidenced by propidium iodide uptake, drop in ATP levels, and absence of LC3-II increase. This was accompanied by a large increase in fatty acids and glycerol in the medium, with levels equivalent to those in aspirates from severe pancreatic necrosis in humans. Orlistat in the medium prevented acinar death and lipolysis and restored responsiveness of repurified acini to stimuli similar to control acini. Individually, unsaturated but not saturated fatty acids at levels present in aspirates from patients with severe pancreatic necrosis increased acinar cytosolic calcium and caused cytochrome C leakage and cell death. We therefore hypothesize that obesity-associated intrapancreatic fat worsens pancreatic injury via unsaturated fatty acids generated from local lipolysis. We propose to study the relative contribution of fatty acids and adipokines to acinar injury and inflammation. We additionally propose to identify the lipase(s) responsible for acinar injury. We will also compare the relevance of obesity to isolated IPF with and without fibrosis with regard to its impact on the severity of AP. These studies could open a new therapeutic frontier for this devastating disease by targeting specific lipases(s) and by stratifying patients according to risk of severe AP based on findings of IPF on imaging studies.
Funding Period: 2011-07-06 - 2016-04-30
more information: NIH RePORT

Top Publications

  1. pmc Lipotoxicity causes multisystem organ failure and exacerbates acute pancreatitis in obesity
    Sarah Navina
    Department of Pathology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA
    Sci Transl Med 3:107ra110. 2011
  2. pmc Ryanodine receptors contribute to bile acid-induced pathological calcium signaling and pancreatitis in mice
    Sohail Z Husain
    Department of Pediatrics, Children s Hospital of Pittsburgh of University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA
    Am J Physiol Gastrointest Liver Physiol 302:G1423-33. 2012
  3. pmc Bile acids induce pancreatic acinar cell injury and pancreatitis by activating calcineurin
    Kamaldeen A Muili
    Department of Pediatrics, Children s Hospital of Pittsburgh of University of Pittsburgh Medical Center and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA
    J Biol Chem 288:570-80. 2013
  4. pmc Fibrosis reduces severity of acute-on-chronic pancreatitis in humans
    Chathur Acharya
    Department of Medicine, University of Pittsburgh Medical Center Passavant, Pittsburgh, Pennsylvania, USA
    Gastroenterology 145:466-75. 2013
  5. pmc Issues in hypertriglyceridemic pancreatitis: an update
    John Scherer
    Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA Division of Gastroenterology, St Peters University Hospital, New Brunswick, NJ
    J Clin Gastroenterol 48:195-203. 2014
  6. pmc Potential influence of intravenous lipids on the outcomes of acute pancreatitis
    Krutika S Patel
    Division of Gastroenterology, Mayo Clinic, Scottsdale, Arizona
    Nutr Clin Pract 29:291-4. 2014
  7. pmc Acute lipotoxicity regulates severity of biliary acute pancreatitis without affecting its initiation
    Chandra Durgampudi
    Department of Medicine, University of Pittsburgh Medical Center Pasavant, Pittsburgh, Pennsylvania
    Am J Pathol 184:1773-84. 2014

Detail Information

Publications7

  1. pmc Lipotoxicity causes multisystem organ failure and exacerbates acute pancreatitis in obesity
    Sarah Navina
    Department of Pathology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA 15213, USA
    Sci Transl Med 3:107ra110. 2011
    ..Thus, therapeutic approaches that target unsaturated fatty acid-mediated lipotoxicity may reduce adverse outcomes in obese patients with critical illnesses such as severe acute pancreatitis...
  2. pmc Ryanodine receptors contribute to bile acid-induced pathological calcium signaling and pancreatitis in mice
    Sohail Z Husain
    Department of Pediatrics, Children s Hospital of Pittsburgh of University of Pittsburgh Medical Center and University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA
    Am J Physiol Gastrointest Liver Physiol 302:G1423-33. 2012
    ..05). These results suggest that the severity of biliary pancreatitis may be ameliorated by the clinical use of RyR inhibitors...
  3. pmc Bile acids induce pancreatic acinar cell injury and pancreatitis by activating calcineurin
    Kamaldeen A Muili
    Department of Pediatrics, Children s Hospital of Pittsburgh of University of Pittsburgh Medical Center and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA
    J Biol Chem 288:570-80. 2013
    ....
  4. pmc Fibrosis reduces severity of acute-on-chronic pancreatitis in humans
    Chathur Acharya
    Department of Medicine, University of Pittsburgh Medical Center Passavant, Pittsburgh, Pennsylvania, USA
    Gastroenterology 145:466-75. 2013
    ..The amount of intrapancreatic fat (IPF) is increased in obese patients and fibrosis is increased in patients with CP, so we studied whether fibrosis or fat regulate severity of AP attacks in patients with CP...
  5. pmc Issues in hypertriglyceridemic pancreatitis: an update
    John Scherer
    Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA Division of Gastroenterology, St Peters University Hospital, New Brunswick, NJ
    J Clin Gastroenterol 48:195-203. 2014
    ..Control of TG levels to 500 mg/dL or less can effectively prevent recurrences of pancreatitis...
  6. pmc Potential influence of intravenous lipids on the outcomes of acute pancreatitis
    Krutika S Patel
    Division of Gastroenterology, Mayo Clinic, Scottsdale, Arizona
    Nutr Clin Pract 29:291-4. 2014
    ..We discuss the clinical and experimental data on this issue and the alternative lipid emulsions that are being studied. ..
  7. pmc Acute lipotoxicity regulates severity of biliary acute pancreatitis without affecting its initiation
    Chandra Durgampudi
    Department of Medicine, University of Pittsburgh Medical Center Pasavant, Pittsburgh, Pennsylvania
    Am J Pathol 184:1773-84. 2014
    ..Inhibition of lipolysis reduces UFA generation and improves these outcomes of AP without interfering with its induction. ..

Research Grants31

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. Mechanisms of Renal Lipotoxicity and Injury in Obesity and Diabetes
    Jesus H Dominguez; Fiscal Year: 2013
    ..This is one of the major problems in diabetes- obesity that afflicts our veteran's population. ..
  3. Metabolic changes in ovarian cancer cells initiated by metastasis to adipose tiss
    Ernst Lengyel; Fiscal Year: 2013
    ..We ultimately hope our experiments will lead us to an improved understanding of OvCa metabolism upon which to build rational therapies that can interfere with the metabolic pathways regulating metastasis. ..
  4. Pathogenesis of Novel Forms of Osteogenesis Imperfecta
    BRENDAN HL LEE; Fiscal Year: 2013
    ..The human genetic studies will supported by the Genomics Core led by Dr. D. Cohn. The implementation and integration of the work will be supported by Dr. B. Lee in the Administrative Core. ..
  5. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  6. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  7. Adipose Tissue Lipolysis and Alcoholic Fatty Liver
    Zhanxiang Zhou; Fiscal Year: 2013
    ..This project will test our hypothesis that reverse fatty acid transport due to excess lipolysis of the adipose tissue plays a crucial role in the pathogenesis of alcoholic fatty liver. ..
  8. The Wake Forest Center for Botanical Lipids and Inflammatory Disease Prevention
    Floyd H Chilton; Fiscal Year: 2013
    ....
  9. REGIONAL FATTY ACID METABOLISM IN HUMANS
    Michael D Jensen; Fiscal Year: 2013
    ..We will measure how fat storage is regulated by specific fat cell proteins in humans according to their body shape, hormone status, and whether they take medications for diabetes. ..
  10. Center for Excellence in Diabetes and Obesity Research
    ARUNI BHATNAGAR BHATNAGAR; Fiscal Year: 2013
    ..Continued support to the Center will strengthen the infrastructure of biomedical research at the University of Louisville and will positively impact the field of diabete and obesity research worldwide. ..
  11. FFA Production From Triglyceride-Rich Lipoproteins
    John M Miles; Fiscal Year: 2013
    ....
  12. Caloric Restricted Rodent Colony
    RICK MORIN; Fiscal Year: 2013
    ..The purpose of this project is to develop, maintain and distribute a standing colony ofaged, calorically restricted rodents ofdefined strains for use by investigators in studies of aging. ..
  13. Role of hemeoxygenase-1 in experimental acute pancreatitis
    Aida Habtezion; Fiscal Year: 2013
    ..Findings from this project could lead to a better understanding of disease pathogenesis and mechanisms for immune cell recruitment to the inflamed pancreas. ..
  14. Adipogenic Toxicity Study of Obesogenic Drugs
    Yuanxiang Zhao; Fiscal Year: 2013
    ..Furthermore, it will help establish prototypes of testing modules for predicting adipogenic toxicity of a wide range of existing drugs in the market, drugs in development, as well as environmental chemicals. ..
  15. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  16. The role of cigarette smoke toxin and alcohol in pancreatitis
    Edwin C Thrower; Fiscal Year: 2013
    ..Findings from this proposal could be broadly relevant to pancreatitis and other diseases in which smoking and alcohol might act together to cause pathology and could also lead to therapeutic targets. ..
  17. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  18. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  19. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  20. Lipid Binding Proteins in Obesity and Diabetes Syndromes
    David A Bernlohr; Fiscal Year: 2013
    ..3. Evaluate the interaction of FABPs with LTA4 and LTA4 metabolizing enzymes. 4. Examine the effects of leukotrienes on macrophage and adipocyte signal transduction and cytokine synthesis. ..
  21. High throughput screens for fatty acid uptake inhibitors
    Concetta C DiRusso; Fiscal Year: 2013
    ....
  22. Regulation of Liver by Nuclear Ca2+ Signaling
    Michael H Nathanson; Fiscal Year: 2013
    ..abstract_text> ..
  23. Ryanodine Receptor in Pancreatitis
    Sohail Z Husain; Fiscal Year: 2013
    ..abstract_text> ..
  24. Relative Contribution of Trypsin &Inflammation in Acute &Chronic Pancreatitis
    Ashok K Saluja; Fiscal Year: 2013
    ..A better understanding of the complex mechanisms will be useful for developing future novel treatments. ..
  25. Obesity, Biomechanics, and Inflammation in Osteoarthritis
    Farshid Guilak; Fiscal Year: 2013
    ..The results of this study will provide new insight into key elements of the pathogenesis of OA, and ultimately could lead to new treatments that exploit physical, dietary, and molecular therapies to prevent disease. ..