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Homocysteine modulates 5-lipoxygenase expression level via DNA methylation.
Aging Cell. 2017 04; 16(2):273-280.AC

Abstract

Elevated levels of homocysteinemia (Hcy), a risk factor for late-onset Alzheimer's disease (AD), have been associated with changes in cell methylation. Alzheimer's disease is characterized by an upregulation of the 5-lipoxygenase (5LO), whose promoter is regulated by methylation. However, whether Hcy activates 5LO enzymatic pathway by influencing the methylation status of its promoter remains unknown. Brains from mice with high Hcy were assessed for the 5LO pathway and neuronal cells exposed to Hcy implemented to study the mechanism(s) regulating 5LO expression levels and the effect on amyloid β formation. Diet- and genetically induced high Hcy resulted in 5LO protein and mRNA upregulation, which was associated with a significant increase of the S-adenosylhomocysteine (SAH)/S-adenosylmethionine ratio, and reduced DNA methyltrasferases and hypomethylation of 5-lipoxygenase DNA. In vitro studies confirmed these results and demonstrated that the mechanism involved in the Hcy-dependent 5LO activation and amyloid β formation is DNA hypomethylation secondary to the elevated levels of SAH. Taken together these findings represent the first demonstration that Hcy directly influences 5LO expression levels and establish a previously unknown cross talk between these two pathways, which is highly relevant for AD pathogenesis. The discovery of such a novel link not only provides new mechanistic insights in the neurobiology of Hcy, but most importantly new therapeutic opportunities for the individuals bearing this risk factor for the disease.

Authors+Show Affiliations

Department of Pharmacology and Center for Translational Medicine, Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA.Department of Pharmaceutical Sciences, Temple University Philadelphia, Philadelphia, PA, 19140, USA.Cancer Biology Program Fox Chase Cancer Center, Temple University Philadelphia, Philadelphia, PA, 19140, USA.Cancer Biology Program Fox Chase Cancer Center, Temple University Philadelphia, Philadelphia, PA, 19140, USA.Department of Pharmaceutical Sciences, Temple University Philadelphia, Philadelphia, PA, 19140, USA.Department of Pharmacology and Center for Translational Medicine, Lewis Katz School of Medicine, Philadelphia, PA, 19140, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

27896923

Citation

Li, Jian-Guo, et al. "Homocysteine Modulates 5-lipoxygenase Expression Level Via DNA Methylation." Aging Cell, vol. 16, no. 2, 2017, pp. 273-280.
Li JG, Barrero C, Gupta S, et al. Homocysteine modulates 5-lipoxygenase expression level via DNA methylation. Aging Cell. 2017;16(2):273-280.
Li, J. G., Barrero, C., Gupta, S., Kruger, W. D., Merali, S., & Praticò, D. (2017). Homocysteine modulates 5-lipoxygenase expression level via DNA methylation. Aging Cell, 16(2), 273-280. https://doi.org/10.1111/acel.12550
Li JG, et al. Homocysteine Modulates 5-lipoxygenase Expression Level Via DNA Methylation. Aging Cell. 2017;16(2):273-280. PubMed PMID: 27896923.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Homocysteine modulates 5-lipoxygenase expression level via DNA methylation. AU - Li,Jian-Guo, AU - Barrero,Carlos, AU - Gupta,Sapna, AU - Kruger,Warren D, AU - Merali,Salim, AU - Praticò,Domenico, Y1 - 2016/11/29/ PY - 2016/10/27/accepted PY - 2016/11/30/pubmed PY - 2017/6/20/medline PY - 2016/11/30/entrez KW - 5-lipoxygenase KW - Alzheimer's disease KW - S-adenosylmethionine KW - amyloid beta KW - homocysteine KW - methylation SP - 273 EP - 280 JF - Aging cell JO - Aging Cell VL - 16 IS - 2 N2 - Elevated levels of homocysteinemia (Hcy), a risk factor for late-onset Alzheimer's disease (AD), have been associated with changes in cell methylation. Alzheimer's disease is characterized by an upregulation of the 5-lipoxygenase (5LO), whose promoter is regulated by methylation. However, whether Hcy activates 5LO enzymatic pathway by influencing the methylation status of its promoter remains unknown. Brains from mice with high Hcy were assessed for the 5LO pathway and neuronal cells exposed to Hcy implemented to study the mechanism(s) regulating 5LO expression levels and the effect on amyloid β formation. Diet- and genetically induced high Hcy resulted in 5LO protein and mRNA upregulation, which was associated with a significant increase of the S-adenosylhomocysteine (SAH)/S-adenosylmethionine ratio, and reduced DNA methyltrasferases and hypomethylation of 5-lipoxygenase DNA. In vitro studies confirmed these results and demonstrated that the mechanism involved in the Hcy-dependent 5LO activation and amyloid β formation is DNA hypomethylation secondary to the elevated levels of SAH. Taken together these findings represent the first demonstration that Hcy directly influences 5LO expression levels and establish a previously unknown cross talk between these two pathways, which is highly relevant for AD pathogenesis. The discovery of such a novel link not only provides new mechanistic insights in the neurobiology of Hcy, but most importantly new therapeutic opportunities for the individuals bearing this risk factor for the disease. SN - 1474-9726 UR - https://www.unboundmedicine.com/medline/citation/27896923/Homocysteine_modulates_5_lipoxygenase_expression_level_via_DNA_methylation_ L2 - https://doi.org/10.1111/acel.12550 DB - PRIME DP - Unbound Medicine ER -