Carboxyl Ester Lipase May Not Mediate Lipotoxic Injury during Severe Acute Pancreatitis

Khatua, Biswajit; Trivedi, Ram N.; Noel, Pawan; Patel, Krutika; Singh, Ravinder J.; Oliveira, Cristiane de; Trivedi, Shubham; Mishra, Vivek; Lowe, Mark E.; Singh, Vijay

doi:10.1016/j.ajpath.2019.02.015

Cited by 18 publications

(17 citation statements)

References 90 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…EGTA has previously been shown to increase LA-induced Cai [24]. These findings that CaE reduces lipotoxic injury were confirmed in the kidney cell line HEK293 ( Figure 2G), which has been previously used to model renal injury in severe pancreatitis [36]. CaE dose-dependently neutralized the toxicity of LA ( Figure 2G) in these, similar to pancreatic acini ( Figure 2B).…”

Section: Physiologically Relevant Extracellular Calcium (Cae) Unlikesupporting

confidence: 64%

Ringer’s Lactate Prevents Early Organ Failure by Providing Extracellular Calcium

Khatua

Yaron

El-Kurdi

et al. 2020

JCM

Self Cite

View full text Add to dashboard Cite

Objective: Ringer’s lactate may improve early systemic inflammation during critical illnesses like severe acute pancreatitis, which are associated with hypocalcemia. Ringer’s lactate is buffered and contains lactate and calcium. We, thus analyzed extracellular calcium or lactate’s effects on the mechanisms, intermediary markers, and organ failure in models mimicking human disease with nonesterified fatty acid (NEFA) elevation. Methods: Meta-analyses and experimental studies were performed. Experimentally, extracellular calcium and lactate were compared in their interaction with linoleic acid (LA; a NEFA increased in human severe pancreatitis), and its subsequent effects on mitochondrial depolarization and cytosolic calcium signaling resulting in cell injury. In vivo, the effect of LA was studied on organ failure, along with the effect of calcium or lactate (pH 7.4) on severe acute pancreatitis-associated organ failure. A meta-analysis of human randomized control trials comparing Ringer’s lactate to normal saline was done, focusing on necrosis and organ failure. Results: Calcium reacted ionically with LA and reduced lipotoxic necrosis. In vivo, LA induced organ failure and hypocalcemia. During severe pancreatitis, calcium supplementation in saline pH 7.4, unlike lactate, prevented hypocalcemia, increased NEFA saponification, reduced circulating NEFA and C-reactive protein, reduced pancreatic necrosis adjacent to fat necrosis, and normalized shock (carotid pulse distension) and blood urea nitrogen elevation on day 1. This, however, did not prevent the later increase in serum NEFA which caused delayed organ failure. Meta-analysis showed Ringer’s lactate reduced necrosis, but not organ failure, compared with normal saline. Conclusion: Hypocalcemia occurs due to excess NEFA binding calcium during a critical illness. Ringer’s lactate’s early benefits in systemic inflammation are by the calcium it provides reacting ionically with NEFA. This, however, does not prevent later organ failure from sustained NEFA generation. Future studies comparing calcium supplemented saline resuscitation to Ringer’s lactate may provide insights to this pathophysiology.

show abstract

Section: Physiologically Relevant Extracellular Calcium (Cae) Unlikesupporting

confidence: 64%

Ringer’s Lactate Prevents Early Organ Failure by Providing Extracellular Calcium

Khatua

Yaron

El-Kurdi

et al. 2020

JCM

Self Cite

View full text Add to dashboard Cite

show abstract

“…Pharmacological inhibition or genetic deletion of ATGL is not sufficient to prevent adipocyte-induced lipotoxic acinar injury. As previously shown, NEFAs injure pancreatic acini (14,59) and other cell types such as the kidney cell line HEK293 (40). To initially identify the lipase(s) mediating the cell injury resulting from fat necrosis, we used a previously described method (14,43).…”

Section: Resultsmentioning

confidence: 99%

“…Pancreatic necrosis collections are enriched in NEFAs with 16 or more carbons such as OA and LA (14,34,60). Triglycerides esterified to these long-chain fatty acids serve as poor substrates for the bile salt-dependent CEL (38)(39)(40). Thus, we focused our attention on PNLIP (black/white/gray) and PNLIPRP2 (burgundy/brownish green) by comparing their relative contributions in lipolytic release of lipotoxic mediators relevant to acute pancreatitis ( Figure 5).…”

Section: Resultsmentioning

confidence: 99%

“…However, PNLIPRP2's clinical relevance is likely to be low because about 50% of Europeans are heterozygous and 20% homozygous for a common PNLIPRP2 truncation variant that results in nonsense-mediated decay, thus inhibiting expression of PNLIPRP2 at the mRNA level (70). Because CEL cannot effectively hydrolyze triglycerides with fatty acids of greater than 16 carbon chains (38,39) and requires bile acid concentrations much higher than in pancreatic necrosis collections (40), it is unlikely to play a major role in fat necrosis. The protection afforded in the PNLIP-KO acini and in mice is unique because PNLIP does not interfere with mechanisms initiating pancreatitis such as caerulein-induced increases in cytosolic calcium or trypsinogen activation (Figure 8, A and C).…”

Section: Discussionmentioning

confidence: 99%

“…For this we used in vitro and in vivo models of acute pancreatitis, and tested the efficacy of the specific ATGL inhibitor Atglistatin (35), an adipocyte-specific ATGL deletion (36), or genetic deletion of PNLIP (37) in preventing the cascade of lipolysis resulting in organ failure. Because CEL cannot hydrolyze long-chain triglycerides, such as those present in visceral fat (38)(39)(40), it was not studied here.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations