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Impact of Sex and Age on the Mevalonate Pathway in the Brain: a Focus on Effects Induced by Maternal Exposure to Exogenous Compounds

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Impact of Sex and Age on the Mevalonate Pathway in the Brain: a Focus on Effects Induced by Maternal Exposure to Exogenous Compounds H OH metabolites OH Review Impact of Sex and Age on the Mevalonate Pathway in the Brain: A Focus on Effects Induced by Maternal Exposure to Exogenous Compounds Claudia Tonini 1 , Marco Segatto 2 and Valentina Pallottini 1,* 1 Department of Science, Roma Tre University, Viale Marconi 446, 00146 Rome, Italy; [email protected] 2 Department of Bioscience and Territory, University of Molise, 86090 Pesche (IS), Italy; [email protected] * Correspondence: [email protected] Received: 15 June 2020; Accepted: 23 July 2020; Published: 25 July 2020 Abstract: The mevalonate pathway produces cholesterol and other compounds crucial for numerous cellular processes. It is well known that age and sex modulate this pathway in the liver. Recently,similar effects were also noted in different brain areas, suggesting that alterations of the mevalonate pathway are at the root of marked sex-specific disparities in some neurodevelopmental disorders related to disturbed cholesterol homeostasis. Here, we show how the mevalonate pathway is modulated in a sex-, age- and region-specific manner, and how maternal exposure to exogenous compounds can disturb the regulation of this pathway in the brain, possibly inducing functional alterations. Keywords: ageing; brain; cholesterol; mevalonate pathway; sex 1. Introduction The mevalonate (MVA) pathway produces cholesterol, one of the most important molecules for cellular, tissue, and organism physiology given its crucial structural and metabolic functions. Besides cholesterol, isopentenyl tRNAs, dolichol phosphate, farnesyls, geranylgeranyls, and ubiquinone are also produced by the MVA pathway, and these components are crucial for numerous cellular processes such as transcription, protein N-glycosylation, protein prenylation, and mitochondrial electron transport (Figure1)[1]. Cholesterol is one of the main components of the plasma membrane determining its chemical- physical properties, such as fluidity and stability. Notably, cholesterol is not uniformly distributed in cell membranes, rather it is concentrated in specialized sphingolipid-rich domains called rafts and caveolae, which are involved in signaling across membranes and thus, are important for cellular functions [2,3]. In the adult brain, about 70–80% of cholesterol is present in myelin sheaths made by oligodendrocytes to insulate axons allowing saltatory electrical signal conduction. Moreover, cholesterol is a precursor for steroid hormones and bile acids [4]. Consequently, imbalanced cholesterol metabolism very often causes pathological changes. For instance, it is well-known that cholesterol accumulation at the artery wall is determinant for the pathogenesis of atherosclerosis and cardiovascular diseases (CVDs). On the other hand, inadequate cholesterol production can likewise be fatal. The suppression of cholesterol biosynthesis in neuronal precursor cells during development results in a reduction of brain size and perinatal lethality in rodents [5]. Metabolites 2020, 10, 304; doi:10.3390/metabo10080304 www.mdpi.com/journal/metabolites Metabolites 2020, 10, 304 2 of 15 Metabolites 2020, 10, x FOR PEER REVIEW 2 of 15 FigureFigure 1. Schematic 1. Schematic representation representation of the of mevalonate the mevalo (MVA)nate (MVA) pathway pathway and its and end-product its end-product functions. functions. To maintain proper cholesterol levels, the body employs a large protein network operating in cellularTo andmaintain blood proper compartments. cholesterol Cholesterol levels, the inbody human employs body a can large both protein be synthesized network operating by cells and in obtainedcellular and by foodblood intake. compartments. Although Cholesterol cholesterol synthesisin human occursbody can in all both tissues, be synthesized the liver represents by cells and the centerobtained of cholesterolby food intake. homeostasis: Although it cholesterol contributes synthesis a large fraction occurs in to all the tissues, bodily the cholesterol liver represents pool, and the it helpscenter to of eliminate cholesterol cholesterol homeostasis: by uptake it contributes of lipoproteins, a large storagefraction of to esterified the bodily cholesterol cholesterol and pool, its release and it afterhelps conversion to eliminate into cholesterol bile acids. Cholesterolby uptake synthesisof lipopr isoteins, a complex storage process of esterified that starts withcholesterol the conversion and its ofrelease acetyl-CoA after conversion to 3-hydroxy-3-methylglutaryl-CoA into bile acids. Cholesterol synthesis (HMG-CoA). is a complex Then, HMG-CoAprocess that is starts converted with the to mevalonicconversion acidof acetyl-CoA (MVA) by the to 3-hydroxy-3-methylglutaryl3-hydroxy-3-methylglutaryl-CoA Coenzyme (HMG-CoA). A reductase Then, (HMGCR), HMG-CoA which is representsconverted theto mevalonic rate-limiting acid enzyme (MVA) in by cholesterol the 3-hydroxy-3-methylglutaryl biosynthesis. Subsequently, Coenzyme a series ofA enzymaticreductase reactions(HMGCR), leads which to therepresents production the ofrate-limiting 3-isopenenyl enzyme pyrophosphate, in cholesterol farnesyl biosynthesis. pyrophosphate, Subsequently, squalene, a andseries lanosterol. of enzymatic Finally, reactions a long 19-step leads processto the produc is neededtion to of obtain 3-isopenenyl cholesterol pyrophosphate, [6]. The cellular farnesyl level of cholesterolpyrophosphate, is regulated squalene, by an and efficient lanosterol. feedback Finally, mechanism a long balancing 19-step biosynthesis, process is import needed and to excretion obtain basedcholesterol on a family [6]. The of transcription cellular level factors of cholesterol known as sterolis regulated regulatory by element-bindingan efficient feedback proteins mechanism (SREBPs). Inbalancing sterol-deprived biosynthesis, cells, import SREBPs and precursors excretion are based proteolytically on a family cleaved of transcription to originate factors the N-terminal known as activesterol regulatory fragment (n-SREBP), element-binding which translocatesproteins (SREBPs) into the. In nucleus sterol-deprived and activates cells, the SREBPs transcription precursors of genes are requiredproteolytically for cholesterol cleaved to synthesis originate and the uptake N-terminal [7]. In active addition fragment to long-term (n-SREBP), regulation, which HMGCR translocates also undergoesinto the nucleus phosphorylation and activates/dephosphorylation, the transcription of genes which required affect its for enzyme cholesterol activity synthesis at a shorter and uptake time scale[7]. [6].In A plethoraaddition of experimentalto long-term findings demonstrateregulation, that peripheralHMGCR cholesterolalso homeostasisundergoes isphosphorylation/dephosphorylation, sex- and age-dependent, and this which peculiarity affect its may enzyme be related activity to theat a sex-relatedshorter time incidence scale [6]. ofA cholesterol-dependentplethora of experimental pathologies, findings demonstrate e.g., CVD [8]. that peripheral cholesterol homeostasis is sex- and age-dependent,The blood–brain and this barrier peculiarity (BBB) separatesmay be rela brainted cholesterolto the sex-related from the incidence rest of theof body;cholesterol- thus, thedependent homeostatic pathologies, control e.g., of this CVD compound [8]. in the central nervous system is independent from the periphery,The blood–brain but probably barrier governed (BBB) byseparates the same brain regulatory cholesterol circuits. fromOur the researchrest of the group, body; and thus, other the laboratories,homeostatic recentlycontrol of highlighted this compound that sex in and the aging central can nervous severely system influence is cholesterolindependent metabolism from the alsoperiphery, in the brainbut probably [9–15]. governed by the same regulatory circuits. Our research group, and other laboratories,Here, we recently will illustrate highlighted the sex- that and sex age-dependent and aging can diff erencesseverely in influence cholesterol cholesterol homeostasis, metabolism focusing onalso the in intergenerationalthe brain [9–15]. effects induced by exogenous compounds in the brain. Metabolites 2020, 10, 304 3 of 15 2. Sex- and Age-Dependent Differences of MVA Pathway in the Liver A critical problem associated with aging is the increased occurrence of hypercholesterolemia, which represents an alarming risk factor for CVDs. CVDs display dimorphic features that may depend on sex-dependent regulation of cholesterol homeostasis [16]. It has been observed that the flow through the MVA pathway, and in turn cholesterol biosynthesis, is affected by sex and aging. For instance, hepatic HMGCR content and activity are similar in female and male rats at 8 days of age, whereas they develop sexually distinct features at 15-days and 3-months of age. These differences are due to the elevation of plasma estrogen levels, starting from 15 post-natal days in female rats [17]. However, the lower HMGCR activity in female rats does not lead to a concurrent reduction in plasma cholesterol. This discrepancy is explained by the fact that estrogens balance the suppression of cholesterol biosynthesis by increasing intestinal cholesterol absorption [4,18,19]. The dimorphism in MVA pathway regulation is also present during aging. In the elderly, loss of homeostasis frequently leads to changes in the biochemical composition of the body, and hypercholesterolemia represents one of the most common metabolic alterations occurring with increasing age in humans and pre-clinical experimental models
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