Cholestenoic Acid Is an Important Elimination Product of Cholesterol in the Retina: Comparison of Retinal Cholesterol Metabolism with That in the Brain

Mast, Natalia; Reem, Rachel E.; Bederman, Ilya; Huang, Suber; DiPatre, Pier Luigi; Björkhem, Ingemar; Pikuleva, Irina A.

doi:10.1167/iovs.10-6021

Cited by 87 publications

(141 citation statements)

References 58 publications

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“…When fed regular rodent chow, 2 H cholesterol enrichment was 20 ± 2% and 9 ± 1% in the retina and brain, respectively, at 2 weeks postinjection with 2 H 2 O. When fed the cholesterolcontaining diet, 2 H cholesterol enrichment was 17 ± 3% in the retina and 11 ± 2% in the brain, statistically insignifi cant changes relative to enrichment measured in animals fed and processed as described ( 13 ). Briefl y, after harvesting, organs were dipped quickly in cold phosphate buffer saline, blotted dry, and homogenized in 10 vol (w/v) of 50 mM potassium phosphate buffer (pH 7.2) containing 300 mM sucrose, 0.5 mM dithiothreitol, 10 mM EDTA, 100 g/ml butylhydroxytoluene, and a cocktail of protease inhibitors.…”

Section: Total Tissue Cholesterol Inputmentioning

confidence: 78%

“…[ 2 H 7 ] ␤ -sitosterol was added as an internal standard for cholesterol quantifi cation: 60 nmol per 50 l of serum, 50 nmol per mg of liver protein, 200 nmol per mg of brain protein, and 10 nmol per two retinas. Lipids were extracted by Folch, saponifi ed, and derivatized with 100 l of bis-(trimethylsilyl) trifl uoroacetamide/trimethylchlorosilane ( 13 ). GC/MS analyses were conducted as described ( 13 ) by a 1 l sample injection in split mode (1:12.5); in the case of retinal samples, 2 l was injected.…”

Section: Total Tissue Cholesterol Inputmentioning

confidence: 99%

“…Gas chromatograph conditions for monitoring of cholesterol and acetone were as described ( 13,15 ). Samples were analyzed in selected ion monitoring mode using electron impact ionization.…”

Section: Gc/ms Analysesmentioning

confidence: 99%

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Cholesterol in mouse retina originates primarily from in situ de novo biosynthesis

Lin

Mast

Bederman

et al. 2016

Journal of Lipid Research

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Cholesterol is a ubiquitous lipid present in the retina ( 1 ), a light-sensitive tissue in the back of the eye that mediates the transmission of the visual signal to the brain. Cholesterol maintenance in the retina is still poorly understood but needs to be studied to delineate the link between retinal cholesterol and age-related macular degeneration (AMD) ( 2 ), a blinding disease affecting the elderly of the industrialized world ( 3 ).The retina maintains cholesterol homeostasis by balancing cholesterol input and output ( 4 ). There are two known pathways of retinal cholesterol input: local cholesterol biosynthesis and tissue uptake of systemic cholesterol (i.e., cholesterol-containing lipoprotein particles from the systemic circulation) ( 5-9 ). The relative contributions, and thus signifi cances, of these pathways to the retinal cholesterol pool are unknown, ultimately impeding the prioritization of research directions in studies of retinal cholesterol ( 2 ).In the present work, we capitalized on the methodological approach developed in our previous investigation of cholesterol input to the brain of mice with disrupted blood-brain barrier ( 10 ). This approach is based on the measurement of the rate of total tissue cholesterol input by administering deuterated water to mice. The rate of tissue uptake of systemic cholesterol is then determined in a separate experiment by feeding mice 2 H-labeled cholesterol. The difference between the two rates can be calculated and represents the rate of tissue cholesterol biosynthesis. We applied our approach to the quantifi cation of cholesterol input to mouse retina and, for comparison, characterized cholesterol input to normal mouse brain, which is also a part of the central nervous system. Both the retina and brain contain neurons and glial cells and are separated from the systemic circulation by the blood-retinal Abstract The retina, a thin tissue in the back of the eye, has two apparent sources of cholesterol: in situ biosynthesis and cholesterol available from the systemic circulation. The quantitative contributions of these two cholesterol sources to the retinal cholesterol pool are unknown and have been determined in the present work. A new methodology was used. Mice were given separately deuterium-labeled drinking water and chow containing 0.3% deuterium-labeled cholesterol. In the retina, the rate of total cholesterol input was 21 g of cholesterol/g retina • day , of which 15 g of cholesterol/g retina • day was provided by local biosynthesis and 6 g of cholesterol/g retina • day was uptaken from the systemic circulation. Thus, local cholesterol biosynthesis accounts for the majority (72%) of retinal cholesterol input. We also quantifi ed cholesterol input to mouse brain, the organ sharing important similarities with the retina. The rate of total cerebral cholesterol input was 121 g of cholesterol/g brain • day with local biosynthesis providing 97% of total cholesterol input. Our work addresses a long-standing question in eye research and adds new knowledge to the...

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Section: Total Tissue Cholesterol Inputmentioning

confidence: 78%

Section: Total Tissue Cholesterol Inputmentioning

confidence: 99%

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Cholesterol in mouse retina originates primarily from in situ de novo biosynthesis

Lin

Mast

Bederman

et al. 2016

Journal of Lipid Research

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“…Previously we measured retinal and the RPE content of cholesterol and sterol metabolites generated enzymatically ( 36 ). In the present work, we focused on 7KCh, the nonenzymatic product of cholesterol oxidation, and investigated its possible elimination by CYP27A1.…”

Section: Discussionmentioning

confidence: 99%

Conversion of 7-ketocholesterol to oxysterol metabolites by recombinant CYP27A1 and retinal pigment epithelial cells

Heo

Bederman

Mast

et al. 2011

Journal of Lipid Research

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“…As expected, analysis of the lipidic parameter for the HD group revealed a significant modification of the plasma lipidic profile, with an increase of 1000% in LDL-C, 400% in TC, and 130% in TG levels. Many epidemiological (27) and in vivo studies using wild type and transgenic animals such as mice (1,(28)(29)(30) have supported a strong association between the pathogenesis of AD and circulating LDL-C. Chen et al have shown that increased levels of LDL-C can lead to disturbances in the endolysosome structure in neurons and, following APP internalization, can promote the accumulation of Aβ deposits (31). In our experiment, despite an approximately fourfold increase in TC plasma levels, we observed no marked change in brain TC.…”

Section: Discussionmentioning

confidence: 99%

High Cholesterol Diet Increases Expression of Cholesterol 24-Hydroxylase and BACE1 in Rat Hippocampi: Implications for the Effect of Diet Cholesterol on Memory

Nikasa¹,

Karimi²,

Rajavand³

et al. 2016

Iran Red Crescent Med J

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Background: Abnormal cholesterol homeostasis is associated with the pathogenesis of neurodegenerative disease and cognitive impairment. Objectives: Our objective was to evaluate changes in the expression of proteins related to cognition and cholesterol homeostasis in the hippocampi of rats as well as behavioral modifications following the administration of a cholesterol-rich diet. Methods: In this experimental study, lasting 16 weeks, 20 male Wistar rats (aged 8 weeks) were randomly divided into two groups. One group was fed with a normal diet (ND; n = 10) and the second with a high cholesterol diet (HD; n = 10). The expression of the cognition-related proteins N-methyl-D-aspartate receptor (NMDAR) and beta-secretase 1 (BACE1) and cholesterol 24-hydroxylase (CYP46A1), the key cholesterol hemostasis protein, were determined by an immunoblotting assay in the hippocampus homogenate. The Morris water maze (MWM) test was used to examine cognitive performance. Plasma lipidic parameters, including total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TG), as well as brain TC were measured by colorimetric assay. Results: After a high cholesterol diet had been administered for a period of 16 weeks, a significant increase in TC, LDL-C and TG was observed in the HD group in comparison with the ND group (P < 0.05). Neither the mean of brain wet weight nor brain TC showed significant change in the HD versus the ND group (P = 0.114, P = 0.84, respectively). Despite this fixity, differences in the expression of BACE1 and CYP46A1 were significant (P < 0.05) between the two groups, with high levels of BACE1 and CYP46A1 in the HD group compared with the ND group. These biochemical changes were associated with a significant decrease in the time traveled on a platform quadrant in the HD versus the ND group (P < 0.05) during a spatial memory probe test administered at the same time. Conclusions:The findings show that irregularities in cognitive performance as a result of a high cholesterol diet can be partially mediated by distortion in brain cholesterol homeostasis and processing of the amyloid precursor protein (APP).

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Cholestenoic Acid Is an Important Elimination Product of Cholesterol in the Retina: Comparison of Retinal Cholesterol Metabolism with That in the Brain

Cited by 87 publications

References 58 publications

Cholesterol in mouse retina originates primarily from in situ de novo biosynthesis

Cholesterol in mouse retina originates primarily from in situ de novo biosynthesis

Conversion of 7-ketocholesterol to oxysterol metabolites by recombinant CYP27A1 and retinal pigment epithelial cells

High Cholesterol Diet Increases Expression of Cholesterol 24-Hydroxylase and BACE1 in Rat Hippocampi: Implications for the Effect of Diet Cholesterol on Memory

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