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Review
. 2020 Aug 12;21(16):5775.
doi: 10.3390/ijms21165775.

The Remedial Potential of Lycopene in Pancreatitis through Regulation of Autophagy

Suyun Choi  1 , Hyeyoung Kim  1
Affiliations
Review

The Remedial Potential of Lycopene in Pancreatitis through Regulation of Autophagy

Suyun Choi et al. Int J Mol Sci. .

Abstract

Autophagy is an evolutionarily conserved process that degrades damaged organelles and recycles macromolecules to support cell survival. However, in certain disease states, dysregulated autophagy can play an important role in cell death. In pancreatitis, the accumulation of autophagic vacuoles and damaged mitochondria and premature activation of trypsinogen are shown in pancreatic acinar cells (PACs), which are the hallmarks of impaired autophagy. Oxidative stress mediates inflammatory signaling and cytokine expression in PACs, and it also causes mitochondrial dysfunction and dysregulated autophagy. Thus, oxidative stress may be a mediator for autophagic impairment in pancreatitis. Lycopene is a natural pigment that contributes to the red color of fruits and vegetables. Due to its antioxidant activity, it inhibited oxidative stress-induced expression of cytokines in experimental models of acute pancreatitis. Lycopene reduces cell death through the activation of 5'-AMP-activated protein kinase-dependent autophagy in certain cells. Therefore, lycopene may ameliorate pancreatitis by preventing oxidative stress-induced impairment of autophagy and/or by directly activating autophagy in PACs.

Keywords: autophagy; inflammatory responses; lycopene; oxidative stress; pancreatitis.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Possible mechanisms by which lycopene attenuates the pathology of acute pancreatitis via its effect on autophagy. Various stimuli (alcohol abuse, bile acids due to duct obstruction by gallstones, infection) lead to increased reactive oxygen species (ROS), intracellular and mitochondrial Ca2+ overload, and dysfunction of mitochondria in pancreatic acinar cells (PACs). Activated Ca2+ signaling also stimulates ROS production in PACs. Therefore, ROS may be the critical signaling factor to induce pancreatitis. ROS induce mitochondrial dysfunction, as determined by mitochondrial matrix Ca2+ overload, reduced mitochondrial membrane potential, and low ATP synthesis in PACs. Mitochondrial dysfunction also can be caused by impaired autophagy, with an accumulation of damaged mitochondria. Mitochondrial dysfunction leads to impaired and dysregulated autophagy, including accumulation of autophagic vacuoles/autolysosomes, increased (accumulated) pancreatic LC3-II and p62, decreased autophagic efficiency, decreased rate of long-lived protein degradation (inefficient lysosomal degradation), disruption of ATG7 and LAMP-2 (decreased LAMP-2), and lysosomal dysfunction in PACs. Decreased hydrolase activity, decreased conversion to trypsin from trypsinogen, and deficient autophagic protein degradation are also shown in acute pancreatitis. All of these events result in the premature activation of trypsinogen and trypsin accumulation in PACs, which are the symptoms of acute pancreatitis. Ca2+ overload can directly induce premature activation of trypsinogen. ROS induce ER stress, which increases Ca signaling that may activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to produce ROS in PACs. ROS activate inflammatory signaling (JNK, NF-kB) to induce cytokine expression, leading to pancreatic inflammation. Lycopene inhibits NADPH oxidase activity and thus, reduces ROS levels and/or directly scavenges ROS in stimulated PACs. Lycopene prevents ROS- and Ca2+-induced mitochondrial dysfunction and impaired autophagy. Lycopene can activate AMPK-dependent autophagy, which inhibits cell death. Therefore, lycopene prevents impaired autophagy, which is shown in acute pancreatitis. Therefore, lycopene may potentially serve as a preventive and therapeutic agent for pancreatitis. Red lines: inhibition. AMPK, 5’-AMP-activated protein kinase; ATG, autophagy-related gene; ER stress, endoplasmic reticulum stress; JNK, c-Jun NH2-terminal kinase; LAMP, lysosomal-associated membrane protein; LC3, microtubule-associated 1A/1B-light chain 3; NADPH, nicotinamide adenine dinucleotide phosphate; NF-κB, nuclear factor-κB; PACs, pancreatic acinar cells; ROS, reactive oxygen species.
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