The process of vision is impossible without the photoreceptor cells, which have a unique structure and specific maintenance of cholesterol. Herein we report on the previously unrecognized cholesterol-related pathway in the retina discovered during follow-up characterizations of Cyp27a1 ؊/؊ Cyp46a1 ؊/؊ mice.These animals have retinal hypercholesterolemia and convert excess retinal cholesterol into cholesterol esters, normally present in the retina in very small amounts. We established that in the Cyp27a1 ؊/؊ Cyp46a1 ؊/؊ retina, cholesterol esters are generated by and accumulate in the photoreceptor outer segments (OS), which is the retinal layer with the lowest cholesterol content. Mouse OS were also found to express the cholesterol-esterifying enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT1), but not lecithin-cholesterol acyltransferase (LCAT), and to differ from humans in retinal expression of ACAT1. Nevertheless, cholesterol esters were discovered to be abundant in human OS. We suggest a mechanism for cholesterol ester accumulation in the OS and that activity impairment of ACAT1 in humans may underlie the development of subretinal drusenoid deposits, a hallmark of age-related macular degeneration, which is a common blinding disease. We generated Cyp27a1؊/؊ mice, characterized their retina by different imaging modalities, and confirmed that unesterified cholesterol does accumulate in their OS and that there is photoreceptor apoptosis and OS degeneration in this line. Our results provide insights into the retinal response to local hypercholesterolemia and the retinal significance of cholesterol esterification, which could be cell-specific and both beneficial and detrimental for retinal structure and function.
the blood, APOE is mainly associated with VLDLs, IDLs, and chylomicron remnants (2). In the brain and retina, however, the APOE-containing LPPs are different and have densities similar to those of HDLs (3, 4). APOE mediates lipid transfer by being a recognition ligand for specific cellsurface receptors, which bind and internalize the APOEcontaining LPPs (5) after these particles acquire cholesterol from cells with cholesterol excess. The APOE receptors belong to the LDL receptor (LDLR) family and include LDLR, VLDLR, LDLR-related protein 1 (LRP1), LRP1B, LRP2 (megalin), LRP4 (MEGF7), LRP5, LRP6, LRP8 (APOER2), and LRP11 (SORL1) (6) In humans, APOE exists in three isoforms (2, 3, and 4), which differ in their lipid-binding capacity, ability to integrate into LPP, and affinity for the receptors (7). APOE 4 is a risk factor for Alzheimer's disease, whereas APOE 2 is protective (8-10). Conversely, APOE 4 and 2 decrease and increase risks, respectively, for age-related macular Abstract Apolipoprotein E (APOE) is a component of lipid-transporting particles and a recognition ligand for receptors, which bind these particles. The APOE isoform 2 is a risk factor for age-related macular degeneration; nevertheless, APOE absence in humans and mice does not significantly affect the retina. We found that retinal cholesterol biosynthesis and the levels of retinal cholesterol were increased in Apoe / mice, whereas cholesterol elimination by metabolism was decreased. No focal cholesterol deposits were observed in the Apoe / retina. Retinal proteomics identified the most abundant cholesterol-related proteins in WT mice and revealed that, of these cholesterol-related proteins, only APOA4 had increased expression in the Apoe / retina. In addition, there were changes in retinal abundance of proteins involved in proinflammatory and antiinflammatory responses, cellular cytoskeleton maintenance, vesicular traffic, and retinal iron homeostasis. The data obtained indicate that when APOE is absent, particles containing APOA1, APOA4, and APOJ still transport cholesterol in the intraretinal space, but these particles are not taken up by retinal cells. Therefore, cholesterol biosynthesis inside retinal cells increase, whereas metabolism to oxysterols decreases to prevent cells from cholesterol depletion. These and other compensatory changes underlie only a minor retinal phenotype in Apoe / mice.-Saadane, A. A.
Apolipoprotein D (APOD) is an atypical apolipoprotein with unknown significance for retinal structure and function. Conversely, apolipoprotein E (APOE) is a typical apolipoprotein with established roles in retinal cholesterol transport. Herein, we immunolocalized APOD to the photoreceptor inner segments and conducted ophthalmic characterizations of ApoD −/− and ApoD −/− ApoE −/− mice. ApoD −/− mice had normal levels of retinal sterols but changes in the chorioretinal blood vessels and impaired retinal function. The whole body glucose disposal was impaired in this genotype but the retinal glucose metabolism was unchanged. ApoD −/− ApoE −/− mice had altered sterol profile in the retina but apparently normal chorioretinal vasculature and function. The whole body glucose disposal and retinal glucose utilization were enhanced in this genotype. OB-Rb, both leptin and APOD receptor, was found to be expressed in the photoreceptor inner segments and was at increased abundance in the ApoD −/− and ApoD −/− ApoE −/− retinas. Retinal levels of Glut4 and Cd36, the glucose transporter and scavenger receptor, respectively, were increased as well, thus linking APOD to retinal glucose and fatty acid metabolism and suggesting the APOD-OB-Rb-GLUT4/CD36 axis. In vivo isotopic labeling, transmission electron microscopy, and retinal proteomics provided additional insights into the mechanism underlying the retinal phenotypes of ApoD −/− and ApoD −/− ApoE −/− mice. Collectively, our data suggest that the APOD roles in the retina are context-specific and could determine retinal glucose fluxes into different pathways. APOD and APOE do not play redundant, complementary or opposing roles in the retina, rather their interplay is more complex and reflects retinal responses elicited by lack of these apolipoproteins.
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