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Article ; Online: 7,8-Dihydroxy Efavirenz Is Not as Effective in CYP46A1 Activation In Vivo as Efavirenz or Its 8,14-Dihydroxy Metabolite.

Mast, Natalia / Li, Yong / Pikuleva, Irina A

International journal of molecular sciences

2024 Volume 25, Issue 4

Abstract: ... High ... ...

Abstract	High dose
MeSH term(s)	Female ; Male ; Mice ; Animals ; Cholesterol 24-Hydroxylase/metabolism ; Alzheimer Disease/drug therapy ; Amyloid beta-Peptides ; Benzoxazines/chemistry ; Alkynes/therapeutic use ; Cyclopropanes/therapeutic use ; HIV Infections/drug therapy ; Reverse Transcriptase Inhibitors/pharmacology ; Anti-HIV Agents/therapeutic use
Chemical Substances	Cholesterol 24-Hydroxylase (EC 1.14.14.25) ; efavirenz (JE6H2O27P8) ; Amyloid beta-Peptides ; Benzoxazines ; Alkynes ; Cyclopropanes ; Reverse Transcriptase Inhibitors ; Anti-HIV Agents
Language	English
Publishing date	2024-02-13
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25042242
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Article ; Online: Unbiased Insights into the Multiplicity of the CYP46A1 Brain Effects in 5XFAD Mice Treated with Low Dose Efavirenz.

Mast, Natalia / Butts, Makaya / Pikuleva, Irina A

Journal of lipid research

2024 , Page(s) 100555

Abstract: CYP46A1 is the CNS-specific cholesterol 24-hydroxylase that controls cholesterol elimination and turnover in the brain. In mouse models, pharmacologic CYP46A1 activation with low dose efavirenz (EFV) or by gene therapy mitigates the manifestations of ... ...

Abstract	CYP46A1 is the CNS-specific cholesterol 24-hydroxylase that controls cholesterol elimination and turnover in the brain. In mouse models, pharmacologic CYP46A1 activation with low dose efavirenz (EFV) or by gene therapy mitigates the manifestations of various brain disorders, neurologic and non-neurologic, by affecting numerous, apparently unliked biological processes. Accordingly, CYP46A1 is emerging as a promising therapeutic target; however, the mechanisms underlying the multiplicity of the brain CYP46A1 activity effects are currently not understood. We proposed the chain reaction hypothesis, according to which CYP46A1 is important for the three primary (unifying) processes in the brain (sterol flux through the plasma membranes, acetyl-CoA and isoprenoid production), which in turn affect a variety of secondary processes. We already identified several processes secondary to changes in sterol flux and herein undertook a multiomics approach to compare the brain proteome, acetylproteome, and metabolome of 5XFAD mice (an Alzheimer's disease model), control and treated with low dose EFV. We found that the latter had increased production of phospholipids from the corresponding lysophospholipids and a globally increased protein acetylation (including histone acetylation). Apparently, these effects were secondary to increased acetyl-CoA production. Signaling of small GTPases due to their altered abundance or abundance of their regulators could be affected as well, potentially via isoprenoid biosynthesis. In addition, the omics data related differentially abundant molecules to other biological processes either reported previously or new. Thus, we obtained unbiased mechanistic insights and identified potential players mediating the multiplicity of the CYP46A1 brain effects and further detailed our chain reaction hypothesis.
Language	English
Publishing date	2024-05-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1016/j.jlr.2024.100555
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Article ; Online: APOB100 transgenic mice exemplify how the systemic circulation content may affect the retina without altering retinal cholesterol input.

El-Darzi, Nicole / Mast, Natalia / Li, Yong / Pikuleva, Irina A

Cellular and molecular life sciences : CMLS

2024 Volume 81, Issue 1, Page(s) 52

Abstract: Apolipoprotein B (APOB) is a constituent of unique lipoprotein particles (LPPs) produced in the retinal pigment epithelium (RPE), which separates the neural retina from Bruch's membrane (BrM) and choroidal circulation. These LPPs accumulate with age in ... ...

Abstract	Apolipoprotein B (APOB) is a constituent of unique lipoprotein particles (LPPs) produced in the retinal pigment epithelium (RPE), which separates the neural retina from Bruch's membrane (BrM) and choroidal circulation. These LPPs accumulate with age in BrM and contribute to the development of age-related macular degeneration, a major blinding disease. The APOB100 transgenic expression in mice, which unlike humans lack the full-length APOB100, leads to lipid deposits in BrM. Herein, we further characterized APOB100 transgenic mice. We imaged mouse retina in vivo and assessed chorioretinal lipid distribution, retinal sterol levels, retinal cholesterol input, and serum content as well as tracked indocyanine green-bound LPPs in mouse plasma and retina after an intraperitoneal injection. Retinal function and differentially expressed proteins were also investigated. APOB100 transgenic mice had increased serum LDL content and an additional higher density HDL subpopulation; their retinal cholesterol levels (initially decreased) became normal with age. The LPP cycling between the RPE and choroidal circulation was increased. Yet, LPP trafficking from the RPE to the neural retina was limited, and total retinal cholesterol input did not change. There were lipid deposits in the RPE and BrM, and retinal function was impaired. Retinal proteomics provided mechanistic insights. Collectively, our data suggested that the serum LDL/HDL ratio may not affect retinal pathways of cholesterol input as serum LPP load is mainly handled by the RPE, which offloads LPP excess to the choroidal circulation rather than neural retina. Different HDL subpopulations should be considered in studies linking serum LPPs and age-related macular degeneration.
MeSH term(s)	Humans ; Mice ; Animals ; Mice, Transgenic ; Retina ; Retinal Pigment Epithelium ; Cholesterol ; Macular Degeneration/genetics
Chemical Substances	Cholesterol (97C5T2UQ7J)
Language	English
Publishing date	2024-01-22
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-023-05056-4
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Article ; Online: Quantitative characterizations of the cholesterol-related pathways in the retina and brain of hamsters.

Mast, Natalia / El-Darzi, Nicole / Li, Yong / Pikuleva, Irina A

Journal of lipid research

2023 Volume 64, Issue 7, Page(s) 100401

Abstract: The retina and brain are separated from the systemic circulation by the anatomical barriers, which are permeable (the outer blood-retinal barrier) and impermeable (the blood-brain and inner blood-retina barriers) to cholesterol. Herein we investigated ... ...

Abstract	The retina and brain are separated from the systemic circulation by the anatomical barriers, which are permeable (the outer blood-retinal barrier) and impermeable (the blood-brain and inner blood-retina barriers) to cholesterol. Herein we investigated whether whole-body cholesterol maintenance affects cholesterol homeostasis in the retina and brain. We used hamsters, whose whole-body cholesterol handling is more similar to those in humans than in mice, and conducted separate administrations of deuterated water and deuterated cholesterol. We assessed the quantitative significance of the retinal and brain pathways of cholesterol input and compared the results with those from our previous studies in mice. The utility of the measurements in the plasma of deuterated 24-hydroxycholesterol, the major cholesterol elimination product from the brain, was investigated as well. We established that despite a sevenfold higher serum LDL to HDL ratio and other cholesterol-related differences, in situ biosynthesis remained the major source of cholesterol for hamster retina, although its quantitative significance was reduced to 53% as compared to 72%-78% in the mouse retina. In the brain, the principal pathway of cholesterol input was also the same, in situ biosynthesis, accounting for 94% of the total brain cholesterol input (96% in mice); the interspecies differences pertained to the absolute rates of the total cholesterol input and turnover. We documented the correlations between deuterium enrichments of the brain 24-hydroxycholesterol, brain cholesterol, and plasma 24-hydroxycholesterol, which suggested that deuterium enrichment of plasma 24-hydroxycholesteol could be an in vivo marker of cholesterol elimination and turnover in the brain.
MeSH term(s)	Humans ; Cricetinae ; Mice ; Animals ; Deuterium/metabolism ; Cholesterol/metabolism ; Hydroxycholesterols ; Retina/metabolism ; Brain/metabolism ; Homeostasis
Chemical Substances	Deuterium (AR09D82C7G) ; Cholesterol (97C5T2UQ7J) ; Hydroxycholesterols
Language	English
Publishing date	2023-06-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80154-9
ISSN	1539-7262 ; 0022-2275
ISSN (online)	1539-7262
ISSN	0022-2275
DOI	10.1016/j.jlr.2023.100401
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Article ; Online: Increased Acetylcholine Levels and Other Brain Effects in 5XFAD Mice after Treatment with 8,14-Dihydroxy Metabolite of Efavirenz.

Mast, Natalia / Li, Yong / Pikuleva, Irina A

International journal of molecular sciences

2022 Volume 23, Issue 14

Abstract: Efavirenz (EFV), an FDA-approved anti-HIV drug, has off-target binding to CYP46A1, the CNS enzyme which converts cholesterol to 24-hydroxycholesterol. At small doses, EFV allosterically activates CYP46A1 in mice and humans and mitigates some of the ... ...

Abstract	Efavirenz (EFV), an FDA-approved anti-HIV drug, has off-target binding to CYP46A1, the CNS enzyme which converts cholesterol to 24-hydroxycholesterol. At small doses, EFV allosterically activates CYP46A1 in mice and humans and mitigates some of the Alzheimer's disease manifestations in 5XFAD mice, an animal model. Notably, in vitro, all phase 1 EFV hydroxymetabolites activate CYP46A1 as well and bind either to the allosteric site for EFV, neurotransmitters or both. Herein, we treated 5XFAD mice with 8,14-dihydroxyEFV, the binder to the neurotransmitter allosteric site, which elicits the highest CYP46A1 activation in vitro. We found that treated animals of both sexes had activation of CYP46A1 and cholesterol turnover in the brain, decreased content of the amyloid beta 42 peptide, increased levels of acetyl-CoA and acetylcholine, and altered expression of the brain marker proteins. In addition, male mice had improved performance in the Barnes Maze test and increased expression of the acetylcholine-related genes. This work expands our knowledge of the beneficial CYP46A1 activation effects and demonstrates that 8,14-dihydroxyEFV crosses the blood-brain barrier and has therapeutic potential as a CYP46A1 activator.
MeSH term(s)	Acetylcholine/analysis ; Acetylcholine/metabolism ; Alkynes/metabolism ; Alkynes/pharmacology ; Alkynes/therapeutic use ; Alzheimer Disease/drug therapy ; Alzheimer Disease/genetics ; Alzheimer Disease/metabolism ; Amyloid beta-Peptides/genetics ; Amyloid beta-Peptides/metabolism ; Animals ; Benzoxazines/metabolism ; Benzoxazines/pharmacology ; Benzoxazines/therapeutic use ; Brain/drug effects ; Brain/metabolism ; Cholesterol/metabolism ; Cholesterol 24-Hydroxylase/genetics ; Cholesterol 24-Hydroxylase/metabolism ; Cholesterol 24-Hydroxylase/pharmacology ; Cyclopropanes/metabolism ; Cyclopropanes/pharmacology ; Cyclopropanes/therapeutic use ; Disease Models, Animal ; Female ; Male ; Mice
Chemical Substances	Alkynes ; Amyloid beta-Peptides ; Benzoxazines ; Cyclopropanes ; Cholesterol (97C5T2UQ7J) ; Cholesterol 24-Hydroxylase (EC 1.14.14.25) ; efavirenz (JE6H2O27P8) ; Acetylcholine (N9YNS0M02X)
Language	English
Publishing date	2022-07-11
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23147669
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Article ; Online: The Hydroxylation Position Rather than Chirality Determines How Efavirenz Metabolites Activate Cytochrome P450 46A1 In Vitro.

Mast, Natalia / Fotinich, Anna / Pikuleva, Irina A

Drug metabolism and disposition: the biological fate of chemicals

2022 Volume 50, Issue 7, Page(s) 923–930

Abstract: ...

Abstract	(
MeSH term(s)	Alkynes ; Animals ; Benzoxazines/chemistry ; Cholesterol 24-Hydroxylase/chemistry ; Cholesterol 24-Hydroxylase/metabolism ; Cyclopropanes ; Glutamic Acid/metabolism ; Hydroxylation ; Mice
Chemical Substances	Alkynes ; Benzoxazines ; Cyclopropanes ; Glutamic Acid (3KX376GY7L) ; Cholesterol 24-Hydroxylase (EC 1.14.14.25) ; efavirenz (JE6H2O27P8)
Language	English
Publishing date	2022-04-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.122.000874
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Article ; Online: The normalizing effects of the CYP46A1 activator efavirenz on retinal sterol levels and risk factors for glaucoma in Apoj

El-Darzi, Nicole / Mast, Natalia / Li, Yong / Dailey, Brian / Kang, Min / Rhee, Douglas J / Pikuleva, Irina A

Cellular and molecular life sciences : CMLS

2023 Volume 80, Issue 7, Page(s) 194

Abstract: Apolipoprotein J (APOJ) is a multifunctional protein with genetic evidence suggesting an association between APOJ polymorphisms and Alzheimer's disease as well as exfoliation glaucoma. Herein we conducted ocular characterizations of ... ...

Abstract	Apolipoprotein J (APOJ) is a multifunctional protein with genetic evidence suggesting an association between APOJ polymorphisms and Alzheimer's disease as well as exfoliation glaucoma. Herein we conducted ocular characterizations of Apoj
MeSH term(s)	Animals ; Mice ; Sterols ; Clusterin ; Cholesterol 24-Hydroxylase ; Glaucoma/drug therapy ; Glaucoma/genetics
Chemical Substances	Sterols ; Clusterin ; efavirenz (JE6H2O27P8) ; Cholesterol 24-Hydroxylase (EC 1.14.14.25)
Language	English
Publishing date	2023-07-01
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1358415-7
ISSN	1420-9071 ; 1420-682X
ISSN (online)	1420-9071
ISSN	1420-682X
DOI	10.1007/s00018-023-04848-y
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Article ; Online: 2-Hydroxypropyl-β-cyclodextrin reduces retinal cholesterol in wild-type and Cyp27a1

El-Darzi, Nicole / Mast, Natalia / Petrov, Alexey M / Pikuleva, Irina A

British journal of pharmacology

2020 Volume 178, Issue 16, Page(s) 3220–3234

Abstract: Background and purpose: 2-Hydroxypropyl-β-cyclodextrin (HPCD) is an FDA approved vehicle for drug delivery and an efficient cholesterol-lowering agent. HPCD was proposed to lower tissue cholesterol via multiple mechanisms including those mediated by ... ...

Abstract	Background and purpose: 2-Hydroxypropyl-β-cyclodextrin (HPCD) is an FDA approved vehicle for drug delivery and an efficient cholesterol-lowering agent. HPCD was proposed to lower tissue cholesterol via multiple mechanisms including those mediated by oxysterols. CYP27A1 and CYP46A1 are the major oxysterol-producing enzymes in the retina that convert cholesterol to 27- and 24-hydroxycholesterol, respectively. We investigated whether HPCD treatments affected the retina of wild-type and Cyp27a1 Experimental approach: HPCD administration was either by i.p., p.o. or s.c. Delivery to the retina was confirmed by angiography using the fluorescently labelled HPCD. Effects on the levels of retinal sterols, mRNA and proteins were evaluated by GC-MS, qRT-PCR and label-free approach, respectively. Key results: In both wild-type and Cyp27a1 Conclusions and implications: HPCD treatment altered retinal cholesterol homeostasis and is a potential therapeutic approach for the reduction of drusen and subretinal drusenoid deposits, cholesterol-rich lesions and hallmarks of age-related macular degeneration. Linked articles: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.
MeSH term(s)	2-Hydroxypropyl-beta-cyclodextrin ; Animals ; Cholestanetriol 26-Monooxygenase/genetics ; Cholesterol ; Cholesterol 24-Hydroxylase ; Mice ; Oxysterols ; Retina
Chemical Substances	Oxysterols ; 2-Hydroxypropyl-beta-cyclodextrin (1I96OHX6EK) ; Cholesterol (97C5T2UQ7J) ; Cholesterol 24-Hydroxylase (EC 1.14.14.25) ; Cholestanetriol 26-Monooxygenase (EC 1.14.15.15) ; Cyp27a1 protein, mouse (EC 1.14.15.15)
Language	English
Publishing date	2020-08-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80081-8
ISSN	1476-5381 ; 0007-1188
ISSN (online)	1476-5381
ISSN	0007-1188
DOI	10.1111/bph.15209
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Article ; Online: Brain Acetyl-CoA Production and Phosphorylation of Cytoskeletal Proteins Are Targets of CYP46A1 Activity Modulation and Altered Sterol Flux.

Mast, Natalia / Petrov, Alexey M / Prendergast, Erin / Bederman, Ilya / Pikuleva, Irina A

Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics

2021 Volume 18, Issue 3, Page(s) 2040–2060

Abstract: Cholesterol and 24-hydroxycholesterol are the most abundant brain sterols and represent the substrate and product, respectively, of cytochrome P450 46A1 (CYP46A1), a CNS-specific enzyme. CYP46A1 controls cholesterol elimination and turnover in the brain, ...

Abstract	Cholesterol and 24-hydroxycholesterol are the most abundant brain sterols and represent the substrate and product, respectively, of cytochrome P450 46A1 (CYP46A1), a CNS-specific enzyme. CYP46A1 controls cholesterol elimination and turnover in the brain, the two processes that determine the rate of brain sterol flux through the plasma membranes and thereby the properties of these membranes. Brain sterol flux is decreased in Cyp46a1
MeSH term(s)	Acetyl Coenzyme A/genetics ; Acetyl Coenzyme A/metabolism ; Animals ; Brain/metabolism ; Cholesterol 24-Hydroxylase/genetics ; Cholesterol 24-Hydroxylase/metabolism ; Cytoskeletal Proteins/genetics ; Cytoskeletal Proteins/metabolism ; Male ; Metabolomics/methods ; Mice ; Mice, 129 Strain ; Mice, Inbred C57BL ; Mice, Transgenic ; Phosphorylation/physiology ; Sterols/metabolism
Chemical Substances	Cytoskeletal Proteins ; Sterols ; Acetyl Coenzyme A (72-89-9) ; Cholesterol 24-Hydroxylase (EC 1.14.14.25)
Language	English
Publishing date	2021-07-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2316693-9
ISSN	1878-7479 ; 1933-7213
ISSN (online)	1878-7479
ISSN	1933-7213
DOI	10.1007/s13311-021-01079-6
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Article ; Online: Retinal Cholesterol Content Is Reduced in Simvastatin-Treated Mice Due to Inhibited Local Biosynthesis Albeit Increased Uptake of Serum Cholesterol.

Mast, Natalia / Bederman, Ilya R / Pikuleva, Irina A

Drug metabolism and disposition: the biological fate of chemicals

2018 Volume 46, Issue 11, Page(s) 1528–1537

Abstract: Statins, a class of cholesterol-lowering drugs, are currently being investigated for treatment of age-related macular degeneration, a retinal disease. Herein, retinal and serum concentrations of four statins (atorvastatin, simvastatin, pravastatin, and ... ...

Abstract	Statins, a class of cholesterol-lowering drugs, are currently being investigated for treatment of age-related macular degeneration, a retinal disease. Herein, retinal and serum concentrations of four statins (atorvastatin, simvastatin, pravastatin, and rosuvastatin) were evaluated after mice were given a single drug dose of 60 mg/kg body weight. All statins, except rosuvastatin, were detected in the retina: atorvastatin and pravastatin at 1.6 pmol and simvastatin at 4.1 pmol. Serum statin concentrations (pmol/ml) were 223 (simvastatin), 1401 (atorvastatin), 2792 (pravastatin), and 9050 (rosuvastatin). Simvastatin was then administered to mice daily for 6 weeks at 60 mg/kg body weight. Simvastatin treatment reduced serum cholesterol levels by 18% and retinal content of cholesterol and lathosterol (but not desmosterol) by 24% and 21%, respectively. The relative contributions of retinal cholesterol biosynthesis and retinal uptake of serum cholesterol to total retinal cholesterol input were changed as well. These contributions were 79% and 21%, respectively, in vehicle-treated mice and 69% and 31%, respectively, in simvastatin-treated mice. Thus, simvastatin treatment lowered retinal cholesterol because a compensatory upregulation of retinal uptake of serum cholesterol was not sufficient to overcome the effect of inhibited retinal biosynthesis. Simultaneously, simvastatin-treated mice had a 2.9-fold increase in retinal expression of
MeSH term(s)	Animals ; Cholesterol/blood ; Cholesterol/pharmacology ; Female ; Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology ; Lipoproteins, LDL/blood ; Macular Degeneration/blood ; Macular Degeneration/drug therapy ; Male ; Mice ; Mice, Inbred C57BL ; Retina/drug effects ; Retina/metabolism ; Simvastatin/pharmacology ; Up-Regulation/drug effects
Chemical Substances	Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Lipoproteins, LDL ; oxidized low density lipoprotein ; lathosterol (80-99-9) ; Cholesterol (97C5T2UQ7J) ; Simvastatin (AGG2FN16EV)
Language	English
Publishing date	2018-08-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	186795-7
ISSN	1521-009X ; 0090-9556
ISSN (online)	1521-009X
ISSN	0090-9556
DOI	10.1124/dmd.118.083345
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