Cholesterol 24-hydroxylase: Brain cholesterol metabolism and beyond

Moutinho, Miguel; Nunes, Maria João; Rodrigues, Elsa

doi:10.1016/j.bbalip.2016.09.011

Cited by 53 publications

(38 citation statements)

References 129 publications

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“…The major elimination pathway of brain cholesterol is the conversion into 24(S)-hydroxycholesterol (24-OHC), which crosses the blood-brain barrier (BBB), enters the circulation, and is eliminated by the liver. This conversion is carried out by the cholesterol 24-hydroxylase (CYP46A1), an enzyme belonging to the cytochrome P450 family mainly expressed by neurons [17]. During experimental autoimmune encephalomyelitis (EAE), a widely used model of MS, CYP46A1 induction has been described in activated astrocytes, microglia and macrophages inside the demyelination areas.…”

Section: Introductionmentioning

confidence: 99%

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

Marangon

Boccazzi

Lecca

et al. 2020

JCM

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Myelin is an essential structure that protects axons, provides metabolic support to neurons and allows fast nerve transmission. Several neurological diseases, such as multiple sclerosis, are characterized by myelin damage, which is responsible of severe functional impairment. Myelin repair requires the timely recruitment of adult oligodendrocyte precursor cells (OPCs) at the lesion sites, their differentiation and maturation into myelinating oligodendrocytes. As a consequence, OPCs undergo profound changes in their morphology, functions, and interactions with other cells and extracellular environment, thus requiring the reorganization of both their lipid metabolism and their membrane composition, which is substantially different compared to other plasma membranes. Despite the growing knowledge in oligodendroglia biology and in the mechanisms involved in OPC-mediated regeneration, the identification of strategies to promote remyelination still remains a challenge. Here, we describe how altered lipid metabolism in oligodendrocytes influences the pathogenesis of demyelination, and we show that several FDA-approved drugs with a previously unknown remyelination potential do act on cholesterol and lipid biosynthetic pathways. Since the interplay between myelin lipids and axons is strictly coordinated by the extracellular matrix (ECM), we also discuss the role of different ECM components, and report the last findings on new ECM-modifiers able to foster endogenous remyelination.Damage to myelin sheath is present in different severe neurological conditions such as multiple sclerosis (MS), brain ischemia, and amyotrophic lateral sclerosis (ALS). Loss of myelin ultimately results in reduction of nerve conduction velocity and in altered transfer of energy metabolites to neurons which contribute to disease [5,6]. Myelin repair, through the activation, recruitment and differentiation of adult oligodendrocyte precursor cells (OPCs), which become new myelin forming OLs [7], is crucial for limiting axon degeneration and progressive disease disability. During the remyelination process, OPCs undergo profound morphological and functional changes and progressively remodel their membrane composition, increasing the biosynthesis of cholesterol and galactosphingolipids, and reducing the relative amount of phospholipids and proteins [4]. An intricate interaction of environmental signals and cell-intrinsic mechanisms triggered by the immune and inflammatory response to injury is known to limit the regenerative potential of OPCs in MS [8,9]. However, the role of modulators of lipid metabolism in OPC-mediated repair is still not completely elucidated. Of note, recent studies suggest that targeting the lipid pathways in OLs may be a good strategy to promote remyelination [10].Furthermore, in MS, remyelination failure is also strictly correlated to an altered extracellular signaling microenvironment that, among others, affects the organization of OL membranes, which causes defects in myelin at the molecular level [11,12]. Although the ECM is ...

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Section: Introductionmentioning

confidence: 99%

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

Marangon

Boccazzi

Lecca

et al. 2020

JCM

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“…The tight control of the cholesterol concentration and homeostasis is of paramount importance for the functions of all cells of the body but particularly for the brain. More so as the rate of cholesterol accumulation and synthesis is subject to subtle alterations over the lifetime of a human being [4,6]. …”

Section: Introductionmentioning

confidence: 99%

“…To overcome the blood–brain barrier, nature has developed efficient mechanisms to convert cholesterol into metabolites, which can easily diffuse into the brain. These metabolites are primarily the oxysterols (24 S )-hydroxycholesterol (24 S -HC) for the transport from the brain to the bloodstream and 27-hydroxycholesterol (27-HC) for the transport in the opposite direction [4,6,8]. These molecules are modified by a hydroxy group at the alkyl chain end of the cholesterol molecule, introducing a second polar center to the hydrophobic tetracyclic ring system in addition to the OH moiety of cholesterol (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…This putatively simple modification is responsible for the better membrane penetrability (see below, [7]). A very interesting finding is that the plasma level of 24 S -HC, which is nearly exclusively produced in the brain [6], can be used as a marker for neurodegenerative and neurological diseases including Alzheimer’s diseases [4,6,8–9]. …”

Section: Introductionmentioning

confidence: 99%

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Membrane properties of hydroxycholesterols related to the brain cholesterol metabolism

Hilsch

Haralampiev

Müller

et al. 2017

Beilstein J. Org. Chem.

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Compared to cholesterol, hydroxycholesterols contain an additional hydroxy group in the alkyl chain and are able to efficiently cross the brain-blood barrier. Therefore, they are responsible for the sterol transfer between brain and circulation. The current study compares the membrane properties of several hydroxycholesterols with those of cholesterol using 2 H NMR spectroscopy, a membrane permeability assay, and fluorescence microscopy experiments. It is shown that hydroxycholesterols do not exert the unique impact on membrane properties characteristic for cholesterol with regard to the influence on lipid chain order, membrane permeability and formation of lateral domains. 720

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“…[2][3][4][5][6] As an important structural component of myelin as well as membranes of neurons and glial cells, cholesterol plays a central role in the process of dendrite outgrowth and myelination, maintenance of stability of microtubules, and synaptogenesis. 7 In the brain, cholesterol is mainly metabolized into 24S-hydroxylcholesterol (24-HC) by cholesterol 24-hydroxylase (CH24H) for elimination. CH24H is a --- Corresponding author.…”

mentioning

confidence: 99%

Synthesis and pharmacokinetic study of a 11C-labeled cholesterol 24-hydroxylase inhibitor using ‘in-loop’ [11C]CO2 fixation method

Chen

Mast

et al. 2020

Bioorganic & Medicinal Chemistry Letters

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Alzheimer's disease (AD) is a long-term neurodegenerative disorder that ranks sixth in the leading cause of all deaths in the United States and features amyloid β protein (Aβ) deposition and neurofibrillary tangles composed of aggregated phosphorylated tau protein (p-tau). 1 To date, an estimated 6% of 65-year or older people in the world are suffering from AD, which approximately accounts for 95% of AD cases. Despite tremendous research efforts towards AD, the underlying cause of AD remains elusive, and no treatment has been disclosed to stop or reverse the AD progress.

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Cholesterol 24-hydroxylase: Brain cholesterol metabolism and beyond

Cited by 53 publications

References 129 publications

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

Regulation of Oligodendrocyte Functions: Targeting Lipid Metabolism and Extracellular Matrix for Myelin Repair

Membrane properties of hydroxycholesterols related to the brain cholesterol metabolism

Synthesis and pharmacokinetic study of a 11C-labeled cholesterol 24-hydroxylase inhibitor using ‘in-loop’ [11C]CO2 fixation method

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