The Interplay between Retinal Pathways of Cholesterol Output and Its Effects on Mouse Retina

Autor:	Aicha Saadane, Irina A. Pikuleva, Alexey M. Petrov, Natalia Mast, Artem A. Astafev, Nicole El-Darzi
Jazyk:	angličtina
Rok vydání:	2019
Předmět:	0301 basic medicine Apolipoprotein E Male medicine.medical_specialty Mice Knockout ApoE glucose metabolism vesicular traffic Biochemistry Retina Article 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Internal medicine CYP27A1 medicine Animals synaptic function Molecular Biology age-related macular degeneration fatty acid oxidation SOAT1 Cholesterol cilia cholesterol Retinal photoreceptors Sterol Mice Inbred C57BL CYP46A1 030104 developmental biology medicine.anatomical_structure Endocrinology chemistry inflammation oxysterols Female lipids (amino acids peptides and proteins) 030217 neurology & neurosurgery APOE Lipoprotein
Zdroj:	Biomolecules Volume 9 Issue 12
ISSN:	2218-273X
DOI:	10.3390/biom9120867
Popis:	In mammalian retina, cholesterol excess is mainly metabolized to oxysterols by cytochromes P450 27A1 (CYP27A1) and 46A1 (CYP46A1) or removed on lipoprotein particles containing apolipoprotein E (APOE). In contrast, esterification by sterol-O-acyltransferase 1 (SOAT) plays only a minor role in this process. Accordingly, retinal cholesterol levels are unchanged in Soat1&minus /&minus mice but are increased in Cyp27a1&minus Cyp46a1&minus and Apoe&minus mice. Herein, we characterized Cyp27a1&minus Soat1&minus and Cyp27a1&minus Apoe&minus mice. In the former, retinal cholesterol levels, anatomical gross structure, and vasculature were normal, yet the electroretinographic responses were impaired. Conversely, in Cyp27a1&minus mice, retinal cholesterol levels were increased while anatomical structure and vasculature were unaffected with only male mice showing a decrease in electroretinographic responses. Sterol profiling, qRT-PCR, proteomics, and transmission electron microscopy mapped potential compensatory mechanisms in the Cyp27a1&minus retina. These included decreased cholesterol biosynthesis along with enhanced formation of intra- and extracellular vesicles, possibly a reserve mechanism for lowering retinal cholesterol. In addition, there was altered abundance of proteins in Cyp27a1&minus mice that can affect photoreceptor function, survival, and retinal energy homeostasis (glucose and fatty acid metabolism). Therefore, the levels of retinal cholesterol do not seem to predict retinal abnormalities, and it is rather the network of compensatory mechanisms that appears to determine retinal phenotype.
Databáze:	OpenAIRE
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