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

Pharmacol Ther. 2019 Mar:195:100-110. doi: 10.1016/j.pharmthera.2018.10.010.

A D Dobrian ¹, M A Morris ², D A Taylor-Fishwick ³, T R Holman ⁴, Y Imai ⁵, R G Mirmira ⁶, J L Nadler ⁷

Affiliations

1 Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, VA, United States.
2 Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, United States.
3 Department of Microbiology, Cell and Molecular Biology, Eastern Virginia Medical School, Norfolk, VA, United States.
4 Department of Chemistry and Biochemistry, University of California Santa Cruz, Santa Cruz, CA, United States.
5 University of Iowa Carver College of Medicine, Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa, city, IA, United States.
6 Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA; Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
7 Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, United States. Electronic address: [email protected].

PMID: 30347209 DOI: 10.1016/j.pharmthera.2018.10.010

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.

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