Lipotoxicity Causes Multisystem Organ Failure and Exacerbates Acute Pancreatitis in Obesity

Abstract

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.

Fatty Acid Ethyl Esters Are Less Toxic Than Their Parent Fatty Acids Generated during Acute Pancreatitis

“…It has been previously shown that ATP levels drop in response to LA over 1 hour. 35 Similar to the pattern of LDH leakage, and the previously published data, 11,35 LA and OA resulted in significantly lower ATP levels, whereas their corresponding EEs (LAEE and OAEE had higher levels ( Figure 1C). We also noted cytochrome c leakage to be more with the FAs than with the corresponding FAEEs ( Figure 1D).…”

“…As previously published, we noted maximal Ca i increase at 600 mmol/L, which is in the range noted in human pancreatic necrosis collections. 11,32 Consistent with the loss of Jm being associated with triggering cell death, there was a greater increase in the 530/590 emission ratio of JC-1 induced by LA and OA than by LAEE or OAEE (Figure 2, A and B) at equal concentrations. Similarly, LA and OA (Figure 2, C and D) did cause an increase in Ca i , but LAEE and OAEE did not.…”

“…These NEFA concentrations used are within the range of those noted in human pancreatic necrosis collections. 11,12,32 Although both UFAs (LA and OA) resulted in >50% LDH leakage, their respective EEs (LAEE and OAEE) resulted in significantly less acinar injury. Because UFAs are known to eventually induce acinar necrosis, 11e13 we measured PI uptake and noted a similar pattern ( Figure 1B).…”

“…Serum OA (C18:1) level was measured by performing nonesterified FA (NEFA) analysis with the use of gas chromatography, as described previously, 11,12,35 on samples with adequate volumes (at least 25 mL).…”

“…To determine the relative toxicities of FAEEs and the parent NEFAs, 300 mmol/L of the most prevalent NEFAs in the human pancreatic necrosis collections 11,20,32 were added at relevant concentrations to acinar cells, and LDH leakage was measured over 4 hours ( Figure 1A). These NEFA concentrations used are within the range of those noted in human pancreatic necrosis collections.…”