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Research ArticleArticle

Retinal Cholesterol Content Is Reduced in Simvastatin-Treated Mice Due to Inhibited Local Biosynthesis Albeit Increased Uptake of Serum Cholesterol

Natalia Mast, Ilya R. Bederman and Irina A. Pikuleva
Drug Metabolism and Disposition November 2018, 46 (11) 1528-1537; DOI: https://doi.org/10.1124/dmd.118.083345
Natalia Mast
Departments of Ophthalmology and Visual Sciences (N.M., I.A.P.) and Pediatrics (I.R.B.), Case Western Reserve University, Cleveland, Ohio
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Ilya R. Bederman
Departments of Ophthalmology and Visual Sciences (N.M., I.A.P.) and Pediatrics (I.R.B.), Case Western Reserve University, Cleveland, Ohio
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Irina A. Pikuleva
Departments of Ophthalmology and Visual Sciences (N.M., I.A.P.) and Pediatrics (I.R.B.), Case Western Reserve University, Cleveland, Ohio
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    Fig. 1.

    Chemical structures of statins and statin metabolites investigated in the present work. The dihydroxyheptanoic acid functionality is highlighted in gray.

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    Fig. 2.

    Experimental paradigms for the measurements of steady-state tissue cholesterol levels (A), tissue uptake of dietary cholesterol (B), and tissue cholesterol input comprised of local cholesterol biosynthesis and tissue uptake of the synthesized cholesterol from the systemic circulation (C). The number of animals (n) for each experiment is indicated in parenthesis. CF, rodent chow containing 0.3% cholesterol and 10% peanut oil; D7-CF, rodent chow containing 0.3% deuterated cholesterol and 10% peanut oil; D2O, deuterated water.

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    Fig. 3.

    Quantifications of different statins in mouse serum (A) and retina (B) after a single-dose (60 mg/kg body weight) drug administration by oral gavage (n = 3 mice or 6 eyes per statin). ATR, atorvastatin; 2-HATR, 2-hydroxyatorvastatin; np and p, the retinas of nonperfused and perfused mice, respectively; ND, nondetectable (the limit of drug detection is 0.1 pmol/retina or 20 pmol/ml serum); N-DROS, N-desmethylrosuvastatin; PRV, pravastatin; ROS, rosuvastatin; SHA, simvastatin hydroxyacid; SIM, simvastatin. All data represent the means ± S.D. of the measurements in individual mice.

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    Fig. 4.

    Quantifications of simvastatin (SIM) and simvastatin hydroxyacid (SHA) in the serum (A), retina (B), and brain (C) of mice after the 6-week simvastatin administration (60 mg/kg body weight/day) by oral gavage (n = 3 mice or 6 eyes per statin). ND, nondetectable (the limit of drug detection is 20 pmol/ml of serum, 0.1 pmol/retina, and 0.05 pmol/mg brain protein). All data represent the means ± S.D. of the measurements in individual mice.

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    Fig. 5.

    Sterol quantifications in the serum (A), retina (B), and brain (C) of mice after the 6-week simvastatin administration (60 mg/kg body weight/day) by oral gavage (n = 6 mice per treatment group). SIM, simvastatin-treated mice; VEH, vehicle-treated mice. All data represent the means ± S.D. of the measurements in individual mice. Asterisks are statistically significant changes relative to the vehicle-treated group as assessed by a two-tailed, unpaired Student’s t test (*P ≤ 0.05; ***P ≤ 0.001).

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    Fig. 6.

    Relative tissue enrichment with D7-cholesterol in the serum (A), retina (B), and brain (C) of mice fed for 2 weeks with rodent chow containing 0.3% D7-cholesterol and 10% peanut oil (Fig. 2B). All data represent the means ± S.D. of the measurements in individual mice. Asterisks are statistically significant changes relative to the vehicle-treated group as assessed by a two-tailed, unpaired Student’s t test (**P ≤ 0.01; ***P ≤ 0.001). SIM, simvastatin-treated mice; VEH, vehicle-treated mice.

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    Fig. 7.

    Relative tissue cholesterol enrichment with 2H in the serum (A), retina (B), and brain (C) of mice maintained for 2 weeks on 6% D2O (Fig. 2C). All data represent the means ± S.D. of the measurements in individual mice. Asterisks are statistically significant changes relative to the vehicle-treated group as assessed by a two-tailed, unpaired Student’s t test (***P ≤ 0.001). SIM, simvastatin-treated mice; VEH, vehicle-treated mice.

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    Fig. 8.

    Retinal gene expression in mice after the 6-week simvastatin administration (60 mg/kg body weight/day) by oral gavage. All data represent the means ± S.D. of triplicate measurements on a pooled sample of individual retinas from five mice. Since the error bars represent the technical variability of the measurements, statistical significance of changes in the gene expression could not be assessed. SIM, simvastatin-treated mice; VEH, vehicle-treated mice.

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    TABLE 1

     Primer sequences for quantitative real-time polymerase chain reaction

    GeneForward Primer (5′ to 3′)Reverse Primer (5′ to 3′)
    Cd36TACAGAAGACCTGGGCTTGGGAGAGGCGGGCATAGTATCA
    GapdhAGTCCATGCCATCACTGCCACCCCAGTGAGCTTCCCGTTCAGC
    LdlrACCTGCCGACCTGATGAATTCGCAGTCATGTTCACGGTCACA
    Scarb1TTGGCCTGTTTGTTGGGATGATCGATCTTGCTGAGTCCGT
    Srebp2ATGATCACCCCGACGTTCAGGGTCGCTGCGTTCTGGTATATC
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    TABLE 2

     Calculations for tissue cholesterol biosynthesis and uptake rates

    Line #ParameterSerumRetinaBrain
    VEHSIMVEHSIMVEHSIM
    Cholesterol content
     1Serum, mg/dl; retina and brain, nmol/mg protein16313264.448.8271265
     2µg/g wet tissue2576195212,16311,893
    Treatment with dietary D7-cholesterol
     3D7-cholesterol appearance, 2 wk, %37471.51.80.20.2
     4Tissue cholesterol uptake, 2 wk, %3.83.80.50.5
    Treatment with deuterated water
     5Total 2H cholesterol enrichment, 2 wk, %16121691312
     62H cholesterol enrichment from tissue uptake, 2 wk, %0.70.50.090.06
     7Tissue cholesterol biosynthesis, 2 wk, %15.38.512.911.9
    Summary data
     8Absolute rate of cholesterol input, μg/day/g wet tissue (%)35.7 (100)17.2 (100)116.9 (100)106.0 (100)
     9Local biosynthesis, μg/day/g wet tissue (%)28.2 (79)11.9 (69)112.2 (96)101.4 (96)
     10Uptake from blood, μg/day/g wet tissue, (%)7.5 (21)5.3 (31)4.7 (4)4.6 (4)
     11Tissue cholesterol turnover, days72113104112
    • SIM, simvastatin-treated mice; VEH, vehicle-treated mice.

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Drug Metabolism and Disposition: 46 (11)
Drug Metabolism and Disposition
Vol. 46, Issue 11
1 Nov 2018
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Research ArticleArticle

Statins and the Retina

Natalia Mast, Ilya R. Bederman and Irina A. Pikuleva
Drug Metabolism and Disposition November 1, 2018, 46 (11) 1528-1537; DOI: https://doi.org/10.1124/dmd.118.083345

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Research ArticleArticle

Statins and the Retina

Natalia Mast, Ilya R. Bederman and Irina A. Pikuleva
Drug Metabolism and Disposition November 1, 2018, 46 (11) 1528-1537; DOI: https://doi.org/10.1124/dmd.118.083345
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