Pathways of cholesterol homeostasis in mouse retina responsive to dietary and pharmacologic treatments

Zheng, Weiguang; Mast, Natalia; Saadane, Aïcha; Pikuleva, Irina A.

doi:10.1194/jlr.m053439

Cited by 69 publications

(73 citation statements)

References 78 publications

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“…The treatment rate reduction was even more signifi cant when the post hoc analysis was stratifi ed by the baseline AMD severity and CFH genotype: >4-fold decrease in people with nonadvanced AMD and >12-fold decrease in carriers of CC (Y402H) CFH ( 45 ). These promising results suggest that statins should be reconsidered as therapeutics for AMD and that recent studies in simvastatin treatment in mice ( 41,42 ) along with the fi ndings of the present work may be of human relevance.…”

Section: Discussionmentioning

confidence: 59%

“…Also, there were changes in the retinal cytoarchitecture ( 40 ). In contrast, when a different statin (simvastatin) was delivered orally to mice daily for 7 days, retinal cholesterol was decreased (1.4-fold) as was retinal lathosterol (1.3-fold), believed to be a marker for cholesterol biosynthesis ( 41 ). Consistent with this work are studies in mice fed a high-fat, atherogenic diet that induced functional changes in the retina and ultrastructural changes in the underlying retinal pigment epithelium and Bruch's membrane ( 42 ).…”

Section: Discussionmentioning

confidence: 92%

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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: Discussionmentioning

confidence: 59%

Section: Discussionmentioning

confidence: 92%

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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“…Animals were then sacrificed, and blood was collected in the EDTA-coated tubes for plasma isolation by 1000g centrifugation for 10 minutes at 4°C. The liver was isolated as well as described (Zheng et al, 2015) and used along with plasma for the determination of cholesterol and 27HC content by gas chromatography-mass spectrometry, as described (Zheng et al, 2015).…”

Section: Methodsmentioning

confidence: 99%

Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

2015

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Cytochrome P450 CYP27A1 is the only enzyme in humans converting cholesterol to 27-hydroxycholesterol, an oxysterol of multiple functions, including tissue-specific modulation of estrogen and liver X receptors. Both receptors seem to mediate adverse effects of 27-hydroxycholesterol in breast cancer when the levels of this oxysterol are elevated. The present work assessed druggability of CYP27A1 as a potential antibreast cancer target. We selected 26 anticancer and noncancer medications, most approved by the Food and Drug Administration, and evaluated them first in vitro for inhibition of purified recombinant CYP27A1 and binding to the enzyme active site. Six strong CYP27A1 inhibitors/binders were identified. These were the two antibreast cancer pharmaceuticals anastrozole and fadrozole, antiprostate cancer drug bicalutamide, sedative dexmedetomidine, and two antifungals ravuconazole and posaconazole. Anastrozole was then tested in vivo on mice, which received subcutaneous drug injections for 1 week. Mouse plasma and hepatic 27-hydroxycholesterol levels were decreased 2.6-and 1.6-fold, respectively, whereas plasma and hepatic cholesterol content remained unchanged. Thus, pharmacologic CYP27A1 inhibition is possible in the whole body and individual organs, but does not negatively affect cholesterol elimination. Our results enhance the potential of CYP27A1 as an antibreast cancer target, could be of importance for the interpretation of Femara versus Anastrozole Clinical Evaluation Trial, and bring attention to posaconazole as a potential complementary anti-breast cancer medication. More medications on the US market may have unanticipated off-target inhibition of CYP27A1, and we propose strategies for their identification.

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“…The mouse also is a convenient, affordable, and tractable laboratory animal amenable to both in vivo and in vitro experimental manipulation, including genetic modifi cation, making it an attractive model system to aid our further understanding of cholesterol homeostasis in the retina. With the present publication by Zheng et al ( 12 ), we are further along in this quest than ever before, and as the related recent review by Pikuleva and Curcio promises, " the best is yet to come. "…”

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confidence: 89%

“…In this issue of the Journal of Lipid Research , Zheng et al ( 12 ) provide fundamental information that sheds new light on cholesterol homeostasis in the retina, with insights that have potentially important clinical implications for understanding and possibly treating certain progressive blinding diseases such as age-related macular degeneration. In particular, they focused on transcriptional regulatory mechanisms involved in SREBP [reviewed in ( 2 , 13 )] and LXR/FXR [reviewed in ( 14 )] target gene expression in the mouse, using standard approaches of both dietary (high-fat/high-cholesterol) and pharmacological (simvastatin) manipulation of cholesterol pathway-related genes, as well as treatment with the LXR/ FXR agonist TO901317 ( 15 ).…”

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confidence: 99%

Cholesterol homeostasis in the retina: seeing is believing

Fliesler

2015

Journal of Lipid Research

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Pathways of cholesterol homeostasis in mouse retina responsive to dietary and pharmacologic treatments

Cited by 69 publications

References 78 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

Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy

Cholesterol homeostasis in the retina: seeing is believing

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