The role of lipoxygenases in pathophysiology; new insights and future perspectives

Abstract

Lipoxygenases (LOXs) are dioxygenases that catalyze the formation of corresponding hydroperoxides from polyunsaturated fatty acids such as linoleic acid and arachidonic acid. LOX enzymes are expressed in immune, epithelial, and tumor cells that display a variety of physiological functions, including inflammation, skin disorder, and tumorigenesis. In the humans and mice, six LOX isoforms have been known. 15-LOX, a prototypical enzyme originally found in reticulocytes shares the similarity of amino acid sequence as well as the biochemical property to plant LOX enzymes. 15-LOX-2, which is expressed in epithelial cells and leukocytes, has different substrate specificity in the humans and mice, therefore, the role of them in mammals has not been established. 12-LOX is an isoform expressed in epithelial cells and myeloid cells including platelets. Many mutations in this isoform are found in epithelial cancers, suggesting a potential link between 12-LOX and tumorigenesis. 12R-LOX can be found in the epithelial cells of the skin. Defects in this gene result in ichthyosis, a cutaneous disorder characterized by pathophysiologically dried skin due to abnormal loss of water from its epithelial cell layer. Similarly, eLOX-3, which is also expressed in the skin epithelial cells acting downstream 12R-LOX, is another causative factor for ichthyosis. 5-LOX is a distinct isoform playing an important role in asthma and inflammation. This isoform causes the constriction of bronchioles in response to cysteinyl leukotrienes such as LTC4, thus leading to asthma. It also induces neutrophilic inflammation by its recruitment in response to LTB4. Importantly, 5-LOX activity is strictly regulated by 5-LOX activating protein (FLAP) though the distribution of 5-LOX in the nucleus. Currently, pharmacological drugs targeting FLAP are actively developing. This review summarized these functions of LOX enzymes under pathophysiological conditions in mammals.

Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells

“…1) (Riahi et al, 2010a). Several excellent comprehensive reviews on lipoxygenase classes and isoenzymes and on their biological functions have recently been published Mashima and Okuyama, 2015;Skrzypczak-Jankun et al, 2012). 5-LO derived 5-hydroperoxyeicosatetraenoic acid (5-HpETE) can be transformed by catalytic rearrangement to leukotriene A4 (LTA4), and further transformed to LTB4, LTC4 or to lipoxins.…”

Identification of Differently Metylated Genes Potentially Related to Human Atherosclerosis

“…Полиморфизм по однонуклеотидным заменам пере-численных генов ранее показал связь с атеросклеро-зом и его факторами риска у человека при анализе генетических ассоциаций. С субклиническим атеро-склерозом и осложнениями атеросклероза в виде острых сосудистых событий ассоциирован полимор-физм генов TLR4 и TRAF1 [9,10], а для гена ALOX12 установлена связь с атеросклерозом, сахарным диабе-том 2 типа и артериальной гипертензией [11]. Поли-морфизм генов FABP1 и ABCB11 связан с метаболиче-скими нарушениями (ожирение, метаболический синдром, дислипидемия, неалкогольная жировая болезнь печени) [12,13], а гены TMEM182 и NPR2 -с сосудистыми нарушениями в виде артериальной гипертензии [14,15], ген ALX4 -с сосудисто-метабо-лическими нарушениями в виде сахарного диабета 2 типа [16].…”

Eicosanoids and Inflammation

“…Их эффект близок к действию гистамина и брадики-нина, однако концентрация ЛТЕ, которая необходима для развития типичных проявлений аллергической реакции, в сотни раз меньше [42][43][44].…”

“…Этот ЛТЕ, для которого выделено несколько рецепторов (собственные BLT1, BLT2 и PPARα), привлекает и активирует нейтрофилы, моноциты и лимфоциты, способствуя синтезу цитокинов и антител. Аналогичный эффект оказывает биохимический «родственник» ЛТЕВ5, который является производным ЭПК [21,[42][43][44].…”