24S‐hydroxycholesterol: Cellular effects and variations in brain diseases

Abstract

Cholesterol homeostasis in every tissue is maintained by the delicate mutual regulation between synthesis and catabolism in different cell types. In the mature brain, after myelination has ceased, cholesterol catabolism acquires special relevance to regulate the levels of this lipid, particularly in neurons, because of the general decline of the cholesterol synthesis rate in the brain. The limited synthesis essentially takes place in astrocytes, which have the ability to supply neurons with cholesterol via lipoproptein particles. ATP-binding cassette (ABC) transporters on the astrocyte's plasma membrane are in charge of exporting the synthetized cholesterol to the extracellular milieu. The brain apolipoproteins needed to assemble the lipoprotein particles (ApoE and ApoJ) are also produced and secreted by astrocytes. Ultimately, the lipoprotein particles that carry cholesterol are internalized into neurons after the interaction with surface lipoprotein receptors of the LRP and LDL families (Vitali et al., 2014; Zhang & Liu, 2015) (see Figure 1).Cholesterol synthesis in the brain involves the same molecular reactions than in the liver, being the initial precursor acetyl-CoA.The major regulatory check-point of the cholesterol synthesis is the conversion of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate by the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), a known target of the statins. The transcription of this enzyme is controlled by sterol regulatory element-binding proteins (SREBPs), transcription factors that can bind an sterol-regulatory element (SRE) in the promoter region of the HMGCR gene. The SREBP family is integrated by three isoforms: SREBP-1a, SREBP-1c, and SREBP-2. Among them SREBP-2 is the most abundant in brain tissue (Camargo et al.,

Cholesterol and Alzheimer’s Disease; From Risk Genes to Pathological Effects

“…CYP46A1 converts excess cholesterol to 24S-hydroxycholesterol (24S-OHC) ( Lund et al, 2003 ; Ramirez et al, 2008 ; Zhang and Liu, 2015 ; van der Kant et al, 2019 ), which can be released by neurons and crosses the BBB through diffusion, forming a major export pathway for excess cholesterol from the brain ( Figure 1 ) ( Lütjohann et al, 1996 ; Lund et al, 1999 , 2003 ; Xie et al, 2003 ). Due to its neuron specific origin, 24S-OHC levels in the blood also provide a direct measure of cholesterol turnover levels in the brain ( Sodero, 2020 ). Besides being an export product, as other oxysterols, 24S-OHC can promote ApoE-mediated cholesterol export by activating liver X receptor (LXR) ( Figure 1 ) ( Abildayeva et al, 2006 ; Matsuda et al, 2013 ).…”

Cholesterol dyshomeostasis in amyotrophic lateral sclerosis: cause, consequence, or epiphenomenon?

“…This article is protected by copyright. All rights reserved 24S-OHC and 25-OHC, but not 27-OHC, may be the most harmful to motor neurons [96].…”

Cholesterol Hydroxylating Cytochrome P450 46A1: From Mechanisms of Action to Clinical Applications

“…Similarly, cerebral cholesterol removal is also mainly enzymatic with the major route being 24-hydroxylation catalyzed by cytochrome P450 46A1 or CYP46A1 ( Bjorkhem et al, 1998 ; Lund et al, 2003 ). Studies in humans and mouse models detected changes in CYP46A1 expression or activity in a number of neurodegenerative diseases [Alzheimer’s (AD), Huntington’s (HD), Nieman-Pick type C, spinocerebellar ataxias (Sca), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS)] as well as other brain disorders (epilepsy, autism, Rett syndrome, glioblastoma, and prion infection) ( Figure 1 ; Loftus et al, 1997 ; Boussicault et al, 2016 ; Lopez et al, 2017 ; Grayaa et al, 2018 ; Lütjohann et al, 2018 ; Vejux et al, 2018 ; Han et al, 2019 ; Huang et al, 2019 ; Nobrega et al, 2019 ; Sodero, 2020 ; Steriade et al, 2020 ; Ali et al, 2021 ). Hence, CYP46A1 has emerged as a therapeutic target for these diseases because of its key role in cerebral cholesterol elimination.…”

“…Finally, a list of pressing questions will be offered from the viewpoints of a biochemist (IAP), who pioneered the investigation of CYP46A1 pharmacological modulations and is now identifying brain processes affected by CYP46A1 activity, and a gene therapy neuroscientist (NC), aiming to ultimately bring this therapeutic target to patients affected with severe neurodegenerative diseases. More comprehensive reviews on CYP46A1, oxysterols, and the links between CYP46A1, cholesterol homeostasis in the brain, and neurological disorders can be found elsewhere ( Russell et al, 2009 ; Moutinho et al, 2016 ; Bjorkhem et al, 2019 ; Loera-Valencia et al, 2019 ; Petrov and Pikuleva, 2019 ; Choi and Finlay, 2020 ; Griffiths and Wang, 2020 ; Sodero, 2020 ).…”