Role of the 12-lipoxygenase pathway in diabetes pathogenesis and complications

Abstract

12-lipoxygenase (12-LOX) is one of several enzyme isoforms responsible for the metabolism of arachidonic acid and other poly-unsaturated fatty acids to both pro- and anti-inflammatory lipid mediators. Mounting evidence has shown that 12-LOX plays a critical role in the modulation of inflammation at multiple checkpoints during diabetes development. Due to this, interventions to limit pro-inflammatory 12-LOX metabolites either by isoform-specific 12-LOX inhibition, or by providing specific fatty acid substrates via dietary intervention, has the potential to significantly and positively impact health outcomes of patients living with both type 1 and type 2 diabetes. To date, the development of truly specific and efficacious inhibitors has been hampered by homology of LOX family members; however, improvements in high throughput screening have improved the inhibitor landscape. Here, we describe the function and role of human 12-LOX, and mouse 12-LOX and 12/15-LOX, in the development of diabetes and diabetes-related complications, and describe promise in the development of strategies to limit pro-inflammatory metabolites, primarily via new small molecule 12-LOX inhibitors.

Keywords: Inflammation; Lipoxygenase; Lipoxygenase inhibitors; Type 1 diabetes; Type 2 diabetes-related complications.

Figure 1.. Selective human 12-LOX inhibitors and human 12/15-LOX dual inhibitor.

Shown are the structures of selective human 12-LOX inhibitors: 0-hydroxyquinoline-based ML127 and N-(benzo[d]thiazol-2-yl)-4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide ML355. Also shown is the 12/15-LOX dual inhibitor ML351, which is an amine oxazol.

Figure 2.. Role of 12-LOX and metabolites in beta cell demise.

The figure depicts the pathways activated by 12-LOX in the pancreatic islet beta cell in response to elevated glucose levels, saturated free fatty acids, or PIC. 12-LOX activation leads to the production of pro-inflammatory lipid intermediates (12(S)-hydroperoxyeicosatetraenoic acid and 12(S)-HETE). These intermediates trigger subsequent inflammatory pathways mediated by c-Jun N-terminal kinase, p38-MAPK, and NOX. 12(S)-HETE prevents translocation of Nrf2 as well. Signaling through these pathways leads to increased ROS, oxidative stress, ER stress, which eventually cause beta cell dysfunction and death. Although not depicted in this diagram, other lipid mediators such as LPA and LPC contribute to MCP-1 mediated chemotaxy; ceramides contribute to beta-cell death, etc. FFAR, free fatty acid receptor; PLA, phospholipase A2; PGE₂, prostaglandin E₂; MCP1, monocyte chemoattractant protein 1.

Figure 3.. The complex role of 12- and 15-LOX in exacerbation and resolution of adipose tissue inflammation.

A) Excess consumption of energy demands an increased nutrient storage capacity of adipocytes in white adipose tissue (WAT). As a result, adipocytes become hypertrophic and stressed, leading to dysfunction marked by ensuing inflammation. Expression of pro-inflammatory cytokines, lipocalin-2 (LCN2), renin angiotensin system (RAS) markers, and ER stress markers by these stressed adipocytes and stromal vascular fraction (SVF) of the WAT leads to chronic leukocyte-type 12-LOX (12/15-LOX) activation in the adipocyte and SVF and subsequent generation of pro-inflammatory lipid metabolites, such as 12(S)-HETE and 15(S)-HETE. 12/15-LOX activity promotes further amplification of these pathways, in particular the interleukin-12 (IL-12) pathway. This inflamed fat promotes the recruitment of macrophages and other inflammatory cells into the fat bed, further propagating the inflammatory autocrine cascade. In addition, WAT exerts paracrine and endocrine pro-inflammatory effects through secreted cytokines on various organ systems, including the pancreas, liver, and vasculature, leading to metabolic decline. B) Diets enriched in ω−3 fatty acids or acute inflammatory responses acutely activate the 12- and 15-LOX enzymes in normal or inflamed hypertrophic WAT to generate anti-inflammatory or pro-resolving lipid metabolites, such as the maresins, resolvins, protectins, and lipoxins. Thereby targeting 12/15-LOX activity may be a novel therapeutic target in treating Local WAT and systemic metabolic dysfunction.