{"id":149,"date":"2014-12-07T23:57:23","date_gmt":"2014-12-07T23:57:23","guid":{"rendered":"http:\/\/faculty.washington.edu\/libinxu\/?page_id=149"},"modified":"2019-02-17T17:22:16","modified_gmt":"2019-02-18T01:22:16","slug":"7-dhc-and-slos","status":"publish","type":"page","link":"https:\/\/faculty.washington.edu\/libinxu\/7-dhc-and-slos\/","title":{"rendered":"7-DHC and SLOS"},"content":{"rendered":"\n

7-DHC and SLOS<\/strong><\/p>\n\n\n\n

\"DHC_SLOS\"<\/a><\/figure>\n\n\n\n

3\u03b2-Hydroxysterol-\u03947<\/sup>-reductase (DHCR7; EC 1.3.1.21) catalyzes one of the two parallel last steps of the cholesterol biosynthesis pathway<\/a>. Defects in DHCR7 lead to greatly elevated levels of 7-dehydrocholesterol (7-DHC) and decreased levels of cholesterol in individuals affected with Smith-Lemli-Opitz syndrome (SLOS). The level of 8-DHC is also elevated in SLOS patients due to the functioning of 3\u03b2-hydroxysterol-\u03948<\/sup>,\u03947<\/sup>-isomerase (EBP; EC 5.3.3.5), which catalyzes the equilibration between the \u03948<\/sup>– and the \u03947<\/sup>-double bond. Therapeutic intervention toward SLOS has been focused on cholesterol supplementation, but this approach gives inconsistent results and does not benefit neurological defects. Our recent finds suggest that 7-DHC is prone to free radical oxidation, leading to the formation of over a dozen oxysterol products, many of which have been observed in vivo (see Figure<\/strong> below) [1,2]. Some of these oxysterols are highly cytotoxic and lead to changes in gene expression and cell differentiation.<\/p>\n\n\n\n

\"FreeRadicalOxysterols\"<\/a><\/figure><\/div>\n\n\n\n

7-DHC also serves as an unusual substrate for cytochrome P450 (CYP) 7A1, leading to the cytotoxic 7-ketocholesterol without going through an epoxide [3]. This is a novel pathway of formation for 7-ketocholesterol as cholesterol is the only known precursor to this oxysterol  (mostly via free radical mechanism) before this finding. Recently, 7-DHC was also found to be a substrate of CYP 46A1, leading to the expected 24-OH-7-DHC and the unusual 25-OH-7-DHC (the latter being the favored product) [4]. In addition, 4\u03b1-OH- and 4\u03b2-OH-7-DHC may also be enzymatic products of 7-DHC, and the responsible enzyme(s) are still under investigation [5].<\/p>\n\n\n\n

\"EnzymaticOxysterols\"<\/a><\/figure><\/div>\n\n\n\n

We aim to elucidate the biological actions of these 7-DHC-derived oxysterols by examining the transcriptome and lipidome as oxysterols play central roles in lipid metabolism. We use a combination of neurobiology, mass spectrometry, transcriptomics, and organic synthesis approaches to accomplish the Aims in this project.<\/p>\n\n\n\n

\"\"<\/a><\/figure>\n\n\n\n

The ultimate goal of this project is to develop therapies that target 7-DHC and\/or its oxysterols, ameliorating or eliminating their detrimental effects. Recently, through collaboration with Prof. Steven Fliesler at SUNY-Buffalo, we demonstrated that supplementation of an antioxidant mix (containing vitamin E, vitamin C, and selenite) completely prevented retinal degeneration in AY9944-treated rats, a SLOS model (Fliesler et al. <\/a>Sci. Rep<\/a><\/em>. 2018<\/a>). To our knowledge, this is the first time that an intervention has completely prevented the display of a phenotype associated with SLOS.<\/p>\n\n\n\n

\"\"<\/a><\/figure>\n\n\n\n

References<\/strong><\/p>\n\n\n\n

1. Xu, L.<\/strong>, Davis, T. A., and Porter, N. A. (2009)<\/strong> Rate Constants for Peroxidation of Polyunsaturated Fatty Acids and Sterols in Solution and in Liposomes<\/a>, J. Am. Chem. Soc.<\/em> 131<\/em>, 13037-13044.<\/p>\n\n\n\n

2. Xu, L.<\/strong>,* Korade, Z., Rosado, D. A., Mirnics, K., Porter, N. A.* (2013)<\/strong> Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells<\/a>, J. Lipid Res.<\/em> 54<\/em>, 1135-1143.<\/p>\n\n\n\n

3. Shinkyo, R., Xu, L.<\/strong>, Tallman, K. A., Cheng, Q., Porter, N. A., and Guengerich, F. P. (2011)<\/strong> Conversion of 7-dehydrocholesterol to 7-ketocholesterol is catalyzed by human cytochrome P450 7A1 and occurs by direct oxidation without an epoxide intermediate<\/a>, J. Biol. Chem.<\/em> 286<\/em>, 33021-33028.<\/p>\n\n\n\n

4. Goyal, S., Xiao, Y., Porter, N. A., Xu, L.<\/strong>,* Guengerich, F. P.* (2014)<\/strong> Oxidation of 7-Dehydrocholesterol and Desmosterol by Human Cytochrome P450 46A1<\/a> J. Lipid Res<\/em>. 55<\/em>, 1933-1943.<\/p>\n\n\n\n

5. Xu, L.<\/strong>, Liu, W., Sheflin, L. G., Fliesler, S. J., and Porter, N. A. (2011)<\/strong> Novel oxysterols observed in tissues and fluids of AY9944-treated rats \u2013 a model for Smith-Lemli-Opitz Syndrome<\/a>, J. Lipid Res.<\/em> 52<\/em>, 1810-1820.<\/p>\n\n\n\n

6. Fliesler, S. J.*; Peachey, N. S.; Herron, J.; Hines, K. M.; Weinstock, N. I.; Ramachandra Rao, S.; and Xu, L.<\/u><\/strong>* (2018<\/strong>) <\/strong>Prevention of Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome<\/a>, Sci. Rep.<\/em>, 8<\/em>, 1286.<\/p>\n","protected":false},"excerpt":{"rendered":"

7-DHC and SLOS 3\u03b2-Hydroxysterol-\u03947-reductase (DHCR7; EC 1.3.1.21) catalyzes one of the two parallel last steps of the cholesterol biosynthesis pathway. Defects in DHCR7 lead to greatly elevated levels of 7-dehydrocholesterol (7-DHC) and decreased levels of cholesterol in individuals affected with Smith-Lemli-Opitz syndrome (SLOS). The level of 8-DHC is also elevated in SLOS patients due to […]<\/p>\n","protected":false},"author":1,"featured_media":0,"parent":0,"menu_order":0,"comment_status":"closed","ping_status":"closed","template":"","meta":[],"_links":{"self":[{"href":"https:\/\/faculty.washington.edu\/libinxu\/wp-json\/wp\/v2\/pages\/149"}],"collection":[{"href":"https:\/\/faculty.washington.edu\/libinxu\/wp-json\/wp\/v2\/pages"}],"about":[{"href":"https:\/\/faculty.washington.edu\/libinxu\/wp-json\/wp\/v2\/types\/page"}],"author":[{"embeddable":true,"href":"https:\/\/faculty.washington.edu\/libinxu\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/faculty.washington.edu\/libinxu\/wp-json\/wp\/v2\/comments?post=149"}],"version-history":[{"count":33,"href":"https:\/\/faculty.washington.edu\/libinxu\/wp-json\/wp\/v2\/pages\/149\/revisions"}],"predecessor-version":[{"id":839,"href":"https:\/\/faculty.washington.edu\/libinxu\/wp-json\/wp\/v2\/pages\/149\/revisions\/839"}],"wp:attachment":[{"href":"https:\/\/faculty.washington.edu\/libinxu\/wp-json\/wp\/v2\/media?parent=149"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}