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

A. D. Dobrian, M. A. Morris, D. A. Taylor-Fishwick, T. R. Holman, Y. Imai, R. G. Mirmira, J. L. Nadler

Research output: Contribution to journalReview article

3 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)100-110
Number of pages11
JournalPharmacology and Therapeutics
Volume195
DOIs
StatePublished - Mar 2019

Keywords

  • Inflammation
  • Lipoxygenase
  • Lipoxygenase inhibitors
  • Type 1 diabetes
  • Type 2 diabetes-related complications

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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    Dobrian, A. D., Morris, M. A., Taylor-Fishwick, D. A., Holman, T. R., Imai, Y., Mirmira, R. G., & Nadler, J. L. (2019). Role of the 12-lipoxygenase pathway in diabetes pathogenesis and complications. Pharmacology and Therapeutics, 195, 100-110. https://doi.org/10.1016/j.pharmthera.2018.10.010