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, Raghu Mirmira, J. L. Nadler

Research output: Contribution to journalArticle

1 Citation (Scopus)

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)
JournalPharmacology and Therapeutics
DOIs
StateAccepted/In press - Jan 1 2018

Fingerprint

Arachidonate 12-Lipoxygenase
Diabetes Complications
Protein Isoforms
Lipoxygenase Inhibitors
Unsaturated Fatty Acids
Type 1 Diabetes Mellitus
Arachidonic Acid
Type 2 Diabetes Mellitus
Anti-Inflammatory Agents
Fatty Acids
Inflammation
Lipids
Health
Enzymes

Keywords

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

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

Cite this

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

Role of the 12-lipoxygenase pathway in diabetes pathogenesis and complications. / Dobrian, A. D.; Morris, M. A.; Taylor-Fishwick, D. A.; Holman, T. R.; Imai, Y.; Mirmira, Raghu; Nadler, J. L.

In: Pharmacology and Therapeutics, 01.01.2018.

Research output: Contribution to journalArticle

Dobrian, A. D. ; Morris, M. A. ; Taylor-Fishwick, D. A. ; Holman, T. R. ; Imai, Y. ; Mirmira, Raghu ; Nadler, J. L. / Role of the 12-lipoxygenase pathway in diabetes pathogenesis and complications. In: Pharmacology and Therapeutics. 2018.
@article{c1dbf027c7b142ceaad70630f962553f,
title = "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",
author = "Dobrian, {A. D.} and Morris, {M. A.} and Taylor-Fishwick, {D. A.} and Holman, {T. R.} and Y. Imai and Raghu Mirmira and Nadler, {J. L.}",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.pharmthera.2018.10.010",
language = "English (US)",
journal = "Pharmacology and Therapeutics",
issn = "0163-7258",
publisher = "Elsevier Inc.",

}

TY - JOUR

T1 - Role of the 12-lipoxygenase pathway in diabetes pathogenesis and complications

AU - Dobrian, A. D.

AU - Morris, M. A.

AU - Taylor-Fishwick, D. A.

AU - Holman, T. R.

AU - Imai, Y.

AU - Mirmira, Raghu

AU - Nadler, J. L.

PY - 2018/1/1

Y1 - 2018/1/1

N2 - 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.

AB - 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.

KW - Inflammation

KW - Lipoxygenase

KW - Lipoxygenase inhibitors

KW - Type 1 diabetes

KW - Type 2 diabetes-related complications

UR - http://www.scopus.com/inward/record.url?scp=85055638791&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055638791&partnerID=8YFLogxK

U2 - 10.1016/j.pharmthera.2018.10.010

DO - 10.1016/j.pharmthera.2018.10.010

M3 - Article

C2 - 30347209

AN - SCOPUS:85055638791

JO - Pharmacology and Therapeutics

JF - Pharmacology and Therapeutics

SN - 0163-7258

ER -