title: Lipidomic analysis of the retina in a rat model of Smith-Lemli-Opitz syndrome: alterations in docosahexaenoic acid content of phospholipid molecular species.
abstract: Smith-Lemli-Opitz syndrome (SLOS) is a complex hereditary disease caused by an enzymatic defect in the last step of cholesterol biosynthesis. Progressive retinal degeneration occurs in an AY9944-induced rat model of SLOS, with biochemical and electroretinographic hallmarks comparable with the human disease. We evaluated alterations in the non-sterol lipid components of the retina in this model, compared with age-matched controls, using lipidomic analysis. The levels of 16:0-22:6 and 18:0-22:6 phosphatidylcholine molecular species in retinas were less by > 50% and > 33%, respectively, in rats treated for either 2 or 3 months with AY9944. Relative to controls, AY9944 treatment resulted in > 60% less di-22:6 and > 15% less 18:0-22:6 phosphatidylethanolamine molecular species. The predominant phosphatidylserine (PS) molecular species in control retinas were 18:0-22:6 and di-22:6; notably, AY9944 treatment resulted in > 80% less di-22:6 PS, relative to controls. Remarkably, these changes occurred in the absence of n3 fatty acid deficiency in plasma or liver. Thus, the retinal lipidome is globally altered in the SLOS rat model, relative to control rats, with the most profound changes being less phosphatidylcholine, phosphatidylethanolamine, and PS molecular species containing docosahexaenoic acid (22:6). These findings suggest that SLOS may involve additional metabolic compromise beyond the primary enzymatic defect in the cholesterol pathway.
authors.affiliation: E. A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, Missouri, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Ford
authors.forename: Julie K
authors.initials: JK
authors.lastname: Monda
authors.forename: Richard S
authors.initials: RS
authors.lastname: Brush
authors.forename: Robert E
authors.initials: RE
authors.lastname: Anderson
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Richards
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Fliesler
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000378:metabolism*; D009448:Neurochemistry / Q000379:methods; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010713:Phosphatidylcholines / Q000378:metabolism; D010714:Phosphatidylethanolamines / Q000378:metabolism; D010743:Phospholipids / Q000032:analysis / Q000737:chemistry* / Q000378:metabolism*; D051381:Rats; D012160:Retina / Q000737:chemistry / Q000378:metabolism*; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D019082:Smith-Lemli-Opitz Syndrome / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / Q000494:pharmacology
chemical_list: D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D010743:Phospholipids; D004281:Docosahexaenoic Acids; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride; C483858:phosphatidylethanolamine; D002784:Cholesterol