12-Lipoxygenase Inhibitor Improves Functions of Cytokine-Treated Human Islets and Type 2 Diabetic Islets

Ma, Kaixin; Xiao, An; Park, So Hyun; Glenn, Lindsey; Jackson, Laura; Barot, Tatvam; Weaver, Jessica L.; Taylor‐Fishwick, David A.; Luci, Diane K.; Maloney, David J.; Mirmira, Raghavendra G.; Imai, Yumi; Nadler, Jerry L.

doi:10.1210/jc.2017-00267

Cited by 26 publications

(22 citation statements)

References 34 publications

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“…As such, ML351 would not be an ideal choice for targeting the relevant LOX in human β-cells and macrophages. Conversely, a related drug, ML355, exhibits selectivity for human LOX encoded by ALOX12 ( 21 , 25 ) and appears to have similar effects on reducing human islet ROS production (shown here). Unfortunately, ML355 cannot as yet be tested in preclinical models in vivo.…”

Section: Discussionmentioning

confidence: 63%

“…The absence of such specific and potent inhibitors of the LOX enzymes led members of our group to perform high-throughput screening to identify novel small-molecule inhibitors ( 20 – 23 ). Some of these inhibitors specifically protected β-cell lines and primary mouse and human islets from proinflammatory cytokine-induced dysfunction and death ( 24 , 25 ), but to date, none have been tested in models of diabetes in vivo. ML351 is a small-molecule inhibitor of 12/15-LOX with high potency and selectivity versus other LOX and cyclooxygenase enzymes ( 16 , 17 ).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes

et al. 2017

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Islet β-cell dysfunction and aggressive macrophage activity are early features in the pathogenesis of type 1 diabetes (T1D). 12/15-Lipoxygenase (12/15-LOX) is induced in β-cells and macrophages during T1D and produces proinflammatory lipids and lipid peroxides that exacerbate β-cell dysfunction and macrophage activity. Inhibition of 12/15-LOX provides a potential therapeutic approach to prevent glycemic deterioration in T1D. Two inhibitors recently identified by our groups through screening efforts, ML127 and ML351, have been shown to selectively target 12/15-LOX with high potency. Only ML351 exhibited no apparent toxicity across a range of concentrations in mouse islets, and molecular modeling has suggested reduced promiscuity of ML351 compared with ML127. In mouse islets, incubation with ML351 improved glucose-stimulated insulin secretion in the presence of proinflammatory cytokines and triggered gene expression pathways responsive to oxidative stress and cell death. Consistent with a role for 12/15-LOX in promoting oxidative stress, its chemical inhibition reduced production of reactive oxygen species in both mouse and human islets in vitro. In a streptozotocin-induced model of T1D in mice, ML351 prevented the development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced β-cell oxidative stress, and preservation of β-cell mass. In the nonobese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced β-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in insulitis. The data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of β-cell dysfunction and glycemic deterioration in models of T1D.

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Section: Discussionmentioning

confidence: 63%

Section: Introductionmentioning

confidence: 99%

Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes

et al. 2017

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“…Luci et al, 2010; D. K. Luci et al, 2014; Ma et al, 2017) may represent a novel approach to the treatment and/or prevention of NAFLD, and such inhibitors may augment current approaches to treatment.…”

Section: Resultsmentioning

confidence: 99%

“…12-LOX is detected at low levels in human and mouse islets and treatment of human islets with pro-inflammatory cytokines results in an increase in both 12-LOX activity and protein levels (Chen, Yang, Smith, Carter, & Nadler, 2005). Inhibition of 12-LOX, either genetically or chemically, reverses islet β-cell dysfunction as seen in the presence of pro-inflammatory cytokines and restores normal insulin secretion, alluding to the crucial role played by 12-LOX in preserving insulin secretion during stress (Ma et al, 2017; Tersey et al, 2014). Treatment of human islets with 12-HETE shows a similar reduction in insulin secretion and β-cell dysfunction as seen with pro-inflammatory cytokines, further supporting the role of 12-HETE in islet stress.…”

Section: Nafld Pathogenesismentioning

confidence: 99%

“…Luci et al, 2010; D. K. Luci et al, 2014; Ma et al, 2017) would serve to protect these animals from steatohepatitis. Further studies are needed to confirm the potential of these proposed interventions, particularly given the possibility of off-target effects and non-tissue-specific effects of small molecule drugs of this nature.…”

Section: Available Treatment Modalities For Individuals With Nafldmentioning

confidence: 99%

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Molecular mechanisms of nonalcoholic fatty liver disease: Potential role for 12-lipoxygenase

Samala

Tersey

Anderson³

et al. 2017

Journal of Diabetes and its Complications

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Nonalcoholic fatty liver disease (NAFLD) is a spectrum of pathologies associated with fat accumulation in the liver. NAFLD is the most common cause of liver disease in the United States, affecting up to a third of the general population. It is commonly associated with features of metabolic syndrome, particularly insulin resistance. NAFLD shares the basic pathogenic mechanisms with obesity and insulin resistance, such as mitochondrial, oxidative and endoplasmic reticulum stress. Lipoxygenases catalyze the conversion of poly-unsaturated fatty acids in the plasma membrane—mainly arachidonic acid and linoleic acid—to produce oxidized pro-inflammatory lipid intermediates. 12-Lipoxygenase (12-LOX) has been studied extensively in setting of inflammation and insulin resistance. As insulin resistance is closely associated with development of NAFLD, the role of 12-LOX in pathogenesis of NAFLD has received increasing attention in recent years. In this review we discuss the role of 12-LOX in NAFLD pathogenesis and its potential role in emerging new therapeutics.

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Roles of hydroxyeicosatetraenoic acids in diabetes (HETEs and diabetes)

Dong

Wang²,

Chen³

et al. 2022

Biomedicine & Pharmacotherapy

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12-Lipoxygenase Inhibitor Improves Functions of Cytokine-Treated Human Islets and Type 2 Diabetic Islets

Cited by 26 publications

References 34 publications

Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes

Inhibition of 12/15-Lipoxygenase Protects Against β-Cell Oxidative Stress and Glycemic Deterioration in Mouse Models of Type 1 Diabetes

Molecular mechanisms of nonalcoholic fatty liver disease: Potential role for 12-lipoxygenase

Roles of hydroxyeicosatetraenoic acids in diabetes (HETEs and diabetes)

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