TY - JOUR
T1 - Lipotoxicity causes multisystem organ failure and exacerbates acute pancreatitis in obesity
AU - Navina, Sarah
AU - Acharya, Chathur
AU - DeLany, James P.
AU - Orlichenko, Lidiya S.
AU - Baty, Catherine J.
AU - Shiva, Sruti S.
AU - Durgampudi, Chandra
AU - Karlsson, Jenny M.
AU - Lee, Kenneth
AU - Bae, Kyongtae T.
AU - Furlan, Alessandro
AU - Behari, Jaideep
AU - Liu, Shiguang
AU - McHale, Teresa
AU - Nichols, Larry
AU - Papachristou, Georgios Ioannis
AU - Yadav, Dhiraj
AU - Singh, Vijay P.
PY - 2011/11/2
Y1 - 2011/11/2
N2 - Obesity increases the risk of adverse outcomes during acute critical illnesses such as burns, severe trauma, and acute pancreatitis. Although individuals with more body fat and higher serum cytokines and lipase are more likely to experience problems, the roles that these characteristics play are not clear. We used severe acute pancreatitis as a representative disease to investigate the effects of obesity on local organ function and systemic processes. In obese humans, we found that an increase in the volume of intrapancreatic adipocytes was associated with more extensive pancreatic necrosis during acute pancreatitis and that acute pancreatitis was associated with multisystem organ failure in obese individuals. In vitro studies of pancreatic acinar cells showed that unsaturated fatty acids were proinflammatory, releasing intracellular calcium, inhibiting mitochondrial complexes I and V, and causing necrosis. Saturated fatty acids had no such effects. Inhibition of lipolysis in obese (ob/ob) mice with induced pancreatitis prevented a rise in serum unsaturated fatty acids and prevented renal injury, lung injury, systemic inflammation, hypocalcemia, reduced pancreatic necrosis, and mortality. 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.
AB - Obesity increases the risk of adverse outcomes during acute critical illnesses such as burns, severe trauma, and acute pancreatitis. Although individuals with more body fat and higher serum cytokines and lipase are more likely to experience problems, the roles that these characteristics play are not clear. We used severe acute pancreatitis as a representative disease to investigate the effects of obesity on local organ function and systemic processes. In obese humans, we found that an increase in the volume of intrapancreatic adipocytes was associated with more extensive pancreatic necrosis during acute pancreatitis and that acute pancreatitis was associated with multisystem organ failure in obese individuals. In vitro studies of pancreatic acinar cells showed that unsaturated fatty acids were proinflammatory, releasing intracellular calcium, inhibiting mitochondrial complexes I and V, and causing necrosis. Saturated fatty acids had no such effects. Inhibition of lipolysis in obese (ob/ob) mice with induced pancreatitis prevented a rise in serum unsaturated fatty acids and prevented renal injury, lung injury, systemic inflammation, hypocalcemia, reduced pancreatic necrosis, and mortality. 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.
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U2 - 10.1126/scitranslmed.3002573
DO - 10.1126/scitranslmed.3002573
M3 - Article
C2 - 22049070
AN - SCOPUS:80455129106
SN - 1946-6234
VL - 3
JO - Science translational medicine
JF - Science translational medicine
IS - 107
M1 - 107ra110
ER -