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Review
, 18 (11)

A Mini-Review on the Effect of Docosahexaenoic Acid (DHA) on Cerulein-Induced and Hypertriglyceridemic Acute Pancreatitis

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Review

A Mini-Review on the Effect of Docosahexaenoic Acid (DHA) on Cerulein-Induced and Hypertriglyceridemic Acute Pancreatitis

Yoo Kyung Jeong et al. Int J Mol Sci.

Abstract

Acute pancreatitis refers to the sudden inflammation of the pancreas. It is associated with premature activation and release of digestive enzymes into the pancreatic interstitium and systemic circulation, resulting in pancreatic tissue autodigestion and multiple organ dysfunction, as well as with increased cytokine production, ultimately leading to deleterious local and systemic effects. Although mechanisms involved in pathogenesis of acute pancreatitis have not been completely elucidated, oxidative stress is regarded as a major risk factor. In human acute pancreatitis, lipid peroxide levels in pancreatic tissues increase. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (C22:6n-3), exerts anti-inflammatory and antioxidant effects on various cells. Previous studies have shown that DHA activates peroxisome proliferator-activated receptor-γ and induces catalase, which inhibits oxidative stress-mediated inflammatory signaling required for cytokine expression in experimental acute pancreatitis using cerulein. Cerulein, a cholecystokinin analog, induces intra-acinar activation of trypsinogen in the pancreas, which results in human acute pancreatitis-like symptoms. Therefore, DHA supplementation may be beneficial for preventing or inhibiting acute pancreatitis development. Since DHA reduces serum triglyceride levels, addition of DHA to lipid-lowering drugs like statins has been investigated to reduce hypertriglyceridemic acute pancreatitis. However, high DHA concentrations increase cytosolic Ca2+, which activates protein kinase C and may induce hyperlipidemic acute pancreatitis. In this review, effect of DHA on cerulein-induced and hypertriglyceridemic acute pancreatitis has been discussed. The relation of high concentration of DHA to hyperlipidemic acute pancreatitis has been included.

Keywords: acute pancreatitis; cerulein; docosahexaenoic acid; hyperlipidemia.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Proposed mechanisms of action of docosahexaenoic acid (DHA) in cerulein-induce acute pancreatitis. Cerulein induced the activation of NADPH oxidase, which produces large amounts of reactive oxygen species (ROS) in pancreatic acinar cells. ROS activate protein kinase C-δ (PKC-δ), which activates nuclear factor-κB (NF-κB). ROS also directly activate NF-κB, activator protein-1 (AP-1), janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3), and inflammatory cytokine expression in the cerulein-stimulated pancreatic acinar cells and rat models. The inflammatory events result in development of acute edematous pancreatitis. DHA induces activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) and expression of the PPARγ-target gene, SOD1, and catalase. Since SOD1 and catalase scavenge ROS, DHA inhibits the ROS-mediated activation of inflammatory signaling (PKC-δ, NF-κB, AP-1, JAK2/STAT3) and inflammatory cytokine expression in cerulein-stimulated pancreatic acinar cells and animal models. Antioxidant and anti-inflammatory effects of DHA may be responsible for preventing the development of acute pancreatitis. The bars represent inhibition, while the arrows represent stimulation.
Figure 2
Figure 2
Proposed mechanisms of action of docosahexaenoic acid (DHA) in hypertriglyceridemic and hyperlipidemic acute pancreatitis. DHA inhibits triglyceride (TG) and fatty acid (FA) synthesis in the liver. DHA increases lipoprotein lipase (LPL) activity in the extrahepatic tissues and β-oxidation of FA in the liver and skeletal muscles, thereby contributing to the reduction of FA delivery to the liver and reducing plasma TG levels. High amounts of FAs induce pancreatic inflammation and injury. Therefore, the TG-lowering effect of DHA may prevent hypertriglyceridemic acute pancreatitis. On the other hand, a high concentration of DHA increases Ca2+ and activates PKC isoforms (PKC-α, PKC-δ, PKC-ε, and PKC-ζ) in pancreatic acinar cells, which may induce zymogene activation and pancreatic injury associated with hyperlipidemic acute pancreatitis. In addition, PKC activates NF-κB and induces inflammatory cytokine expression in pancreatic acinar cells. The bars represent inhibition, while the arrows represent stimulation.

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