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  • br The lipoxygenase pathway in

    2024-02-23


    The 12/15-lipoxygenase pathway in diseases of the nervous system
    Conclusions and future perspectives Arachidonic Adenine and other polyunsaturated fatty acids, and their lipid metabolites, play very important roles in human health and disease. This review has outlined the functions of 12- and 15-lipoxygenases, enzymes that are present in multiple systems and organs of the body, including pancreatic islet, adipose, vascular, immune, renal, and nervous tissues. As a result of their widespread expression in the body, 12- and 15-LOX and their metabolites are important in a variety of disease states, including diabetes (both types 1 and 2), atherosclerosis, renal disease, obesity, and various diseases of the central and peripheral nervous system. In all of these areas, the development of isoform specific LOX-inhibitors will be necessary to fully establish the therapeutic opportunity to treat these disorders by reducing expression or activity of 12/15-LOXs. A recent paper has indicated promising new 15-LOX-1 inhibitors have been developed [232]. Much interesting and important work is still needed and underway in this exciting field. Nevertheless, the existing data indicate promise of the 12/15-LOX pathway as a target in a number of disorders, particularly related to diabetes and its complications and in states of insulin resistance.
    Acknowledgements
    Introduction Lipoxygenase is a dioxygenase producing hydroperoxy fatty acids. The enzyme incorporates molecular oxygen into polyunsaturated fatty acids in regio- and stereo-specific manners. In mammalian tissues, there are 5-, 8-, 12- and 15-lipoxygenases named according to the site of oxygenation in arachidonic acid (Brash, 1999, Funk, 1996, Funk, 2001, Kühn and Thiele, 1999, Yoshimoto and Takahashi, 2002). Several isoforms are known in 12-lipoxygenase, namely, leukocyte-type, platelet-type and epidermal-type 12-lipoxygenases producing 12S-hydroperoxy-5, 8, 10, 14-eicosatetraenoic acid as well as 12R-lipoxygenase producing 12-hydroperoxy fatty acid with R configuration (Funk, 2001). The leukocyte-type 12-lipoxygenase is the isoform expressed in a variety of tissues including macrophages. The enzyme shows broad substrate specificity and can directly oxygenate polyunsaturated fatty acids esterified to cholesterol in low-density lipoprotein (LDL) particles (Belkner et al., 1998, Kühn et al., 1994). LDL oxidation is one of the critical steps for atherosclerosis development (Brown and Goldstein, 1990, Steinberg, 2009). Since macrophages expressing high level of leukocyte-type 12-lipoxygenase are accumulated in atherosclerotic lesions (Ylä-Herttuala et al., 1990, Ylä-Herttuala et al., 1991) and capable of causing LDL oxidation (Chisolm, Hazen, Fox, & Cathcart, 1999), the enzyme has been investigated extensively with regard to the contribution to atherogenesis (Takahashi et al., 2005, Zhao and Funk, 2004). It has been proposed that LDL oxidation is initiated by leukocyte-type 12-lipoxygenase by oxygenating linoleate esterified to cholesterol in LDL particles. Subsequent radical chain reactions modify the LDL to its fully oxidized form recognized by scavenger receptors in macrophages that lead to foam cell formation (Belkner et al., 1998, Kühn and Thiele, 1999, Sakashita et al., 1999, Takahashi et al., 2005, Zhao and Funk, 2004). Atherosclerosis development as well as LDL oxidation attenuated in leukocyte-type 12-lipoxygenase-deficient mice clearly demonstrating that the enzyme was required for LDL oxidation (Cyrus et al., 1999, George et al., 2001), although the contradictory study suggested that the atherogenesis was suppressed in the homologous enzyme-transgenic rabbit (Funk, 2001, Shen et al., 1996). We investigated the biochemical mechanism of oxidative modification of extracellular LDL by intracellular leukocyte-type 12-lipoxygenase, and demonstrated that LDL binding to LDL receptor-related protein (LRP), a cell surface receptor expressed on macrophages, but not to LDL receptor was required for the oxidation of LDL (Xu et al., 2001). The LRP mediated the translocation of leukocyte-type 12-lipoxygenase to plasma membranes from cytosol in macrophages which was an essential step for oxidation of LDL (Zhu et al., 2003). Furthermore, LRP contributed to the selective uptake of cholesteryl linoleate from the LDL particle to the cells as well as in the efflux of oxygenated cholesteryl linoleate from the cells to the LDL particles (Takahashi, Zhu, Xu, et al., 2005). The results suggest a critical role of LRP in the process of oxygenation of cholesteryl linoleate in LDL particles by the leukocyte-type 12-lipoxygenase in macrophages (Fig. 1).