Review Article

Cellular Stresses and Stress Responses in the Pathogenesis of Insulin Resistance

Figure 4

Pathways for the hypoxia-induced generation of oxidative and nitrosative stresses through the human circadian locomotor output cycle protein kaput- (hCLOCK-) mediated 12/15-lipoxygenase activation [143150]. 12/15-Lipoxygenase catalyses the production of ROS in the form of 13-hydroperoxy-octadecadienoic acid (13-HPODE) from linoleic acid (LA) or 12-hydroperoxy-eicosatetraenoic acid (12-HPETE) and 15-hydroperoxy-eicosatetraenoic acid (15-HPETE) from arachidonic acid (AA). 13-HPODE, 12-HPETE, and 15-HPETE are reduced to the corresponding hydroxy derivatives 13-HODE, 12-HETE, and 15-HETE, respectively. 13-HPODE, 12-HETE, and 15-HETE activate PKC isoforms [148, 151, 152], which promote activation of NF-κB, NADPH oxidase (Nox) isoforms, and inducible nitric oxide synthase (iNOS) [30, 144150]. iNOS and Nox produce nitric oxide (NO) and superoxide anions (O2·−), respectively, which undergo enzymatic and nonenzymatic reactions that lead to the formation of other ROS such as hydrogen peroxide and singlet oxygen, as well as the RNS, peroxynitrite [30]. 15-HETE activates xanthine oxidase (XO) [154], which catalyses the formation of both superoxide anions and uric acid, and the latter signals via the receptor for advanced glycation end products (RAGE) to activate NF-κB [34].