Elsevier

Medical Hypotheses

Volume 81, Issue 6, December 2013, Pages 1127-1129
Medical Hypotheses

Brain cholesterol homeostasis in Wilson disease

https://doi.org/10.1016/j.mehy.2013.10.018Get rights and content

Abstract

Wilson disease (WD) is an autosomal recessive inherited disorder of copper (Cu) metabolism, resulting in pathological accumulation of Cu in many organs and tissues, predominantly in the liver and brain. There clearly is a close and complex relationship between Cu and the cholesterol’s metabolic pathway; therefore any theory about the cholesterol metabolism in the brain of patients with WD must take it into account.

The hypothesis presented in this paper is that the imbalance in cerebral copper homeostasis caused by WD may plays a key role in the derangement of the cholesterol homeostasis in the brain, and thus promoting the observed WD related neurological disorders.

Introduction

Cholesterol is an essential component of cell membranes and therefore plays an important role in the physical properties of the membrane such as membrane fluidity, membrane permeability and functioning of membrane-associated proteins. Cholesterol is also a precursor of bile acids, and the precursor of all steroid hormones.

The human brain is the most cholesterol-rich organ of the human body, despite occupying only 2% of body mass. Almost 25% of the total unesterified cholesterol of the total body is located there. Within the brain about 70% of cholesterol is present in myelin where it plays mainly a structural role as element of the cell membrane [1]. The remaining 30% of brain cholesterol is divided between glial cells (20%) and neurons (10%) [1].

Cholesterol is organized in microdomains called lipid rafts, which are involved in the maintenance of the properties of membrane proteins such as receptors and ion channels [2]. Since cholesterol is necessary for the formation of synapses [3], proper electrical transmission [4] and serves as a important barrier against sodium leakage [5], cholesterol homeostasis is essential and is tightly regulated by controlling uptake, de novo synthesis, esterification, catabolism (oxidation) and release. Cholesterol also serves as an important source for synaptic plasticity and dendritic formation and remodeling [6]. Recent studies showed that cultured neurons from the mammalian central nervous system (CNS) require glia-derived cholesterol to form numerous and efficient synapses [3], [7], [8].

Unlike cholesterol in other organs in the periphery, brain cholesterol is primarily derived by de novo synthesis. The blood brain barrier (BBB) prevents the uptake of lipoprotein cholesterol from the circulation in vertebrates at the level of tight junction attachments between adjacent capillary endothelial cells [9]. Brain cholesterol represents a distinct in the peripheral circulation, which is efficiently segregated by the BBB.

The biosynthesis of cholesterol may be divided into five stages: (i) synthesis of mevalonate from acetyl-Coenzyme A (CoA); (ii) synthesis of isoprenoid units from mevalonate by loss of CO2; (iii) condensation of six isoprenoid units to form squalene; (iv) cyclization of squalene to give the parental steroid, lanosterol; (v) formation of cholesterol by rearranging the lanosterol molecule. The first committed step in cholesterol biosynthesis is the conversion of 3 molecules of acetyl-CoA to 3-hydroxy-3-methyglutaryl-CoA (HMG-CoA) in the cytosol, followed by the reduction of HMG-CoA to mevalonate. HMG-CoA reductase catalyses this reaction, that is the rate-limiting step in the cholesterol synthesis pathway. Cholesterol homeostasis is maintained by strict regulation of synthesis, uptake and catabolism. Low levels of cholesterol induce the generation of transcription factors leading to increased transcription of target genes, such as HMG-CoA reductase. When cholesterol levels rise, HMG-CoA reductase production is inhibited and thus cholesterol synthesis is reduced.

According to various in vitro studies, astrocytes synthesize at least 5–10-fold more cholesterol than neurons [9]. Neurons appear to produce sufficient amounts of cholesterol to survive, to differentiate axons and dendrites and to form a few and inefficient synapses. The rate of brain cholesterol synthesis declines with brain maturation and age. To preserve a constant level of cholesterol, it has been postulated that in the adult brain, cholesterol is efficiently recycled. Daily sterol turnover in human is about 20-fold lower compared with that in whole body [4]. The estimated half-life of cholesterol in human brains is estimated to be 5 years [10]. In comparison, cholesterol in human plasma has a reported half-life of about 6 days [11]. The massive formation of synapses requires additional cholesterol delivered by astrocytes via ApoE containing lipoprotein [6]. ApoE is the main lipid carrier protein in the CNS and is released by astrocytes in order to supply neurons and synaptogenesis with lipids and cholesterol [12].

In the adult brain most of the synthesis of cholesterol is balanced by formation of a hydroxylated metabolite, 24S-hydroxycholesterol (24OHC), which is able to pass across the BBB and enter into the circulation [13]. Cholesterol is actively converted to 24OHC by cholesterol 24-hydroxylase, a cytochrome P450 (CYP46A1) highly expressed in a subset of neurons in the brain, and subsequently eliminated from brain tissue [14]. This reaction requires oxygen and NADPH. About 6–8 mg/24 h of cholesterol are released as 24OHC by the brain into the circulation [13].

Some evidences suggest that CYP46A1 may have a key role protecting the brain from reactive oxygen species (ROS). ROS can also stimulate the promoter activity of CYP46 in vitro [15]. Disruption of the mouse CYP46A1 gene reduced the synthesis of new cholesterol in the brain by ∼40%, indicating at least 40% of cholesterol turnover in the brain is dependent on the conversion into 24OHC [16]. This knockout mouse exhibited severe deficiencies in spatial, associative, and motor learning, as well as in hippocampal long-term potentiation [17]. In rat model of trauma brain injury was observed an increase of CYP46A1 expression in activated microglia and astrocytes but not in neurons [18]. The expression was higher within and around the lesion area, with progressive reduction by distance [18]. Moreover, neurons with lysosomal cholesterol accumulation are protected from oxidative stress-induced apoptosis [19].

The interaction between Copper (Cu) and cholesterol metabolic pathways in the brain remains to be fully explored. The accumulation of Cu in brain capillaries generates hydroxyl free radical by the Fenton/Haber–Weiss reactions [20], [21]. Cu2+ is reduced to Cu1+ by suitable electron donor (superoxide anion, NADPH, ascorbate, amyloid-β precursor protein, amyloid-β), and Cu1+ in turn reacts with hydrogen peroxide to generate hydroxyl radical, which can cause protein oxidation and lipid peroxidation [22]. There is an increasing appreciation of a role for Cu in normal brain development and function. The importance of Cu for normal brain function is underscored by the profound neurodegeneration in Menkes disease and Wilson disease (WD), rare genetic disorders of Cu deficiency and overload, respectively. More commonly, Cu dyshomeostasis is evident in a number of major neurodegenerative disorders, which include Alzheimer’s disease and Parkinson’s disease.

Imbalance in cerebral Cu homeostasis plays a key role in the pathogenesis of WD [23] and may have direct consequences in the cholesterol homeostasis in the brain. The hallmarks of the disease are the presence of liver disease, neurologic symptoms, and Kayser–Fleischer corneal rings. The leading neurologic symptoms in WD are dysathria, dyspraxia, ataxia, and Parkinsonian-like extrapyramidal signs. Defective in a Cu-dependent P-type ATPase (ATP7B) function results in intra-celluar Cu accumulation, which leads to the hepatic and neurological features of WD [24], [25]. The mechanisms underlying the pathophysiology of WD are not well understood. Established animal models for WD are the Long Evans Cinnamon rat [26], the toxic milk mouse [27], and the Atp7b−/− mouse [28], [29], [30], all showing hepatic copper accumulation. Atp7b−/− mice show a down-regulation of lipid metabolism in the liver, particularly in the cholesterol biosynthesis [31]. Recently, a study in Atp7b−/− mice indicated imbalance of sterol metabolism in the brain [32]. In brain of 3-week-old mice sterols are increased compared to control while decline in 6-week-old mice [32]. In 47-week-old mice sterols are lower than in controls [32]. A similar pattern in the short- and long-term exposure to elevated levels of Cu may be present for 24OHC.

Section snippets

Hypothesis

Based on the information given above, we hypothesize that the high concentration of Cu in the brain of patients with WD may alter the cholesterol homeostasis. The oxidative stress due to the Cu accumulation could enhance the CYP46A1 activity of oxidation of cholesterol into 24OHC.

Testing the hypothesis

In vitro WD models could provide some evidence on the increased biosynthesis of 24OHC for the accumulation of intracellular Cu and, subsequently, Atp7b−/− mice could be used to analyze the 24OHC concentrations in the brain and in the blood.

Imbalance in cerebral Cu homeostasis plays a key role in the pathogenesis of WD, and possibly in other neurodegenerative diseases [33], [34]. While brain cholesterol cannot be measured directly in vivo, 24OHC is the predominant metabolite of brain cholesterol

Consequences of the hypothesis and discussion

Exploring our hypothesis, new knowledge on the biological basis of the neurological disorders development will be generated, which will also help to develop more effective prevention strategies and/or new effective drugs. So, if this hypothesis is confirmed, we will increase the knowledge of biological processes and mechanisms related to development of neurological disorders and this could help changing the current approaches to neurological disorders patients’ management. This may help also to

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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    S.C. was supported by a fellowship from FIRC (Fondazione Italiana per la Ricerca sul Cancro).

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