What Is The Function Of A Cholesterol – Lipid care is a molecule that plays an essential role in many biological, physiological and pathological processes. It is an essential structural component of cell membranes and is fundamental to the biosynthesis, integrity and functions of biological membranes, including membrane communication and signaling. In addition, cholesterol is a major component of lipid rafts, as lipid-based structures that regulate the assembly and operation of several signaling pathways in cells, including those related to cancer, such as tumor growth, adhesion, migration, and invasion; apoptosis Considering the importance of cholesterol metabolism, its homeostasis is strictly regulated at every level: import, synthesis, export, metabolism, and storage. Alterations of this homeostatic balance are known to be associated with cardiovascular disease and atherosclerosis, but mounting evidence also links these behaviors to increased cancer risks. Despite conflicting evidence regarding the role of cholesterol in cancer development, most studies consistently suggest that dysregulation of cholesterol homeostasis could lead to cancer development. This review aims to present the current understanding of cholesterol homeostasis in normal and cancerous cells, summarizing key findings from recent preclinical and clinical studies that have investigated the roles of major players in cholesterol regulation and lipid ratio regulation, which could represent promising therapeutic targets. .
It is a primary lipid molecule that plays an essential role in many biological processes, both at the physiological and pathological levels (Maxfield and Tabas, 2005).
What Is The Function Of A Cholesterol
In addition to being an important constituent of cell membranes, their biogenesis is fundamental and necessary to maintain the integrity and functions of biological membranes, including endocytosis, membrane trafficking and signaling (Maxfield and Tabas, 2005; Yamauchi and Rogers; 2018). Inside the cell, cholesterol, distributed heterogeneously between organelles, modulates the immune system, and represents a precursor to hormones such as sex hormones and vitamin D (Mollined and Gajate, 2020; Figure 1).
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Recently, cholesterol has played a key role in cancer research because of its therapeutic potential and its implications for both prevention and treatment. However, the role of cholesterol in oncogenesis is still debated (DuBroff and de Lorgeril, 2015). The literature has reported contradictory data on the role of cholesterol according to tumor type (Ding et al., 2019). Excess cholesterol is related to breast, colon, rectal, prostate, and testicular cancers (Llaverias et al., 2011; Pelton et al., 2012; Murai, 2015; Radisauskas et al., 2016), while some prospective cohort studies have shown. inverse association in gastric and prostate cancers (Asano et al., 2008; Heir et al., 2016). This review is aimed at the current knowledge of cholesterol homeostasis, critically investigating the most recent preclinical and clinical studies investigating the roles of the main players of the cholesterol biosynthetic pathway, and cholesterol-based membrane lipid balances in the field of cancer.
Treatment takes place through a cascade of enzymatic reactions, namely the mevalonate pathway, which requires the participation of different enzymes localized in the membranes of the endoplasmic reticulum (ER). Briefly, the combination of three molecules of acetyl-CoA leads to the formation of one molecule of 3-hydroxy-3-methylglutamic coenzyme A (HMG-CoA). This, by the action of reduced HMG-CoA (HMGCR), is converted into mevalonate, into squalene (SQL), and finally into cholesterol through several reactions (Figure 2). Food can be a source of cholesterol too. In fact, the Niemann-Pick type C1-like 1 (NPC1L1) protein, present in the membrane of intestinal enterocytes, is responsible for the absorption of cholesterol, which is received as chylomicrons, released as triglyceride-lipid particles. by the liver (Altmann et al., 2004; Luo et al., 2020).
Figure 2. Care biosynthesis pathways and their main inhibitors. Starting with three molecules of acetyl-coenzyme A (CoA), cholesterol is synthesized in more than twenty enzymatic steps. 3-Hydroxy-3-methylglutarium-CoReductase (HMGCR) and squalene epoxidase (SQLE) act as rate-limiting enzymes. The main inhibitors of cholesterol biosynthesis are statins that inhibit HMGCR, inhibitors of sterol regulatory binding protein (SREBP), which inactivate the transcription of cholesterol biosynthesis genes; and bisphosphonates, which act downstream of statins and inhibit farnesyl pyrophosphate synthase with a consequent decrease in farnesyl pyrophosphate and geranylgerany pyrophosphate. This step of cholesterol biosynthesis is also targeted by farnesyl transferase inhibitors.
Cholesterol is mainly synthesized in the liver and released into the bloodstream as very low density lipoproteins (VLDLs). In the bloodstream, VLDLs are transformed to low-density lipoproteins (LDLs), transported to peripheral cells via the bloodstream (Ikonen, 2008; Goldstein and Brown, 2009). LDLs enter cells through receptor (LDLR)-mediated endocytosis and are transported to lysosomes where they are hydrolyzed into free cholesterol molecules, which are transported to cell membranes to carry out their multiple functions (Brown and Goldstein, 1986; Ikonen, 2008; Maxfield and van Meer, 2010). Kuzu et al., 2016).
Why Does Your Body Need Cholesterol?
The mevalonate pathway is tightly regulated by transcriptional and translational mechanisms capable of responding to physiological signals. Biosynthesis is controlled by four main players: (1) sterol regulatory element binding protein 2 (SREBP2), which acts through a negative feedback mechanism (Sato, 2010), (2) liver X receptors (LXRs), (3) HMGCR and (4) squalene epoxidase (SQLE). HMGCR and SQLE are rate-controlling enzymes that can regulate cholesterol biosynthesis, reactions that are energetically expensive to catalyze. When intracellular levels of ATP are low, 5′adenosine monophosphate-activated protein kinase (AMPK) phosphorylates HMGCR inhibiting its function (Loh et al., 2019). However, HMGCR is induced by the presence of LDL in the medium; in fact, during LDL starvation, HMGCR activity increases, while it greatly decreases when LDL is added back. On the other hand, when cholesterol has exhausted its function, its surplus is exported through the ATP binding cassette (ABC) subfamily A member 1 (ABCA1) or ABC subfamily G member 1 (ABCG1) to apolipoprotein A-I (ApoA-I poor lipid) ), thus high-density lipoproteins generating (HDLs) (Gelissen et al., 2006; Lorenzi et al., 2008; Daniil et al., 2013; Phillips, 2014). Transcription of ABCA1 by nuclear LXRs is induced when intracellular cholesterol levels are high (Wang et al., 2008; Ouvrier et al., 2009; Kuzu et al., 2016). CoA:cholesteryl acyltransferase 1 (ACAT1) converts excess cholesterol into less toxic compounds, such as cholesteryl esters (CEs), which are stored as lipid droplets and used to produce plasma lipoproteins (chylomicrons, VLDLs, LDLs and HDLs. ). HDLs are then transported from peripheral tissues to the liver and intestine, to recycle or eliminate cholesterol, and to steroidogenic organs, where cholesterol is used to generate steroid hormones (Chang et al., 2009; Luo et al., 2020).
Recent studies on microRNAs (miRNAs), a class of non-coding RNAs, have highlighted their role in cholesterol homeostasis by regulating some key components of the system (Wagschal et al., 2015). For example, under sterol stress, higher transcription of miR-33a is required to regulate cholesterol export and HDL metabolism through inhibition of ABCA1 (Wagschal et al., 2015). In turn, miR-223 regulates the amount of cholesterol by inhibiting its production and improving cholesterol efflux by increasing the levels of ABCA1 (Vickers et al., 2014). miRNA-122, particularly present in hepatocytes, suppresses blood cholesterol levels when it is significantly inhibited (Rotllan and Fernandez-Hernando, 2012). miR-27a has been shown to regulate HMGCR levels either through posttranslational inhibition or through mRNA degradation (Khan et al., 2020). Notably, other miRNAs were found through meta-analyses to be associated with changes in cholesterol-lipoprotein metabolism, such as miR-128-1, miR-148a, miR-130b, and miR-301b. These miRNAs could increase circulating cholesterol by regulating the expression of LDLR and ABCA1 (Wagschal et al., 2015).
These data suggest the participation of miRNAs in the control of cholesterol metabolism, highlighting how they may contribute to the alteration of dysregulated cholesterol levels.
Considering the importance of cholesterol metabolism, its cellular homeostasis is strictly regulated at all levels: import, synthesis, export, transport and esterification (Ikonen, 2008). Sterol regulatory element binding protein 2 (SREBF2) and LXRs act as key regulators of cholesterol homeostasis (Ikonen, 2008). In the ER, cholesterol itself regulates its homeostasis. Lower cholesterol levels induce the translocation of SREBP2 to the nucleus where it promotes the activation of genes involved in biosynthesis (for example, HMGCR) and cholesterol clearance (Ikonen, 2008). High cholesterol levels inhibit cholesterol synthesis and facilitate its export through the activation of LXRs by oxysterols, derivatives of oxidized cholesterol (Wang et al., 2008; Kuzu et al., 2016). Recent studies have highlighted the important role of LXRs in prostate cancer LNCaP cell protection (Pommier et al., 2010; Fu et al., 2014). In fact, activation of these transcription factors regulating cholesterol homeostasis could induce cell cycle arrest and promote apoptosis (Pommier et al., 2010). The relationship between LXRs, cholesterol, and prostate cancer highlights that LXRs may have a chance to be targeted in this tumor.
Review Of Laboratory Methods To Determine Hdl And Ldl Subclasses And Their Clinical Importance
In cholesterol biosynthesis, depending on the type of tissue, various sterol intermediates are formed, such as cholesteryl ester, oxysterols, bile acids, cholecalciferol/vitamin D, and various steroid hormones. All these sterols have important physiological functions in cells and tissues (Simon and Ikonen, 2000). Some cholesterol metabolites may also contribute to the development and metastasis of some types of cancer (Lin et al., 2013; McDonnell et al., 2014; Baek et al., 2017).
Under healthy conditions, the amount of cholesterol arises from the balance between synthesis, uptake from the extracellular environment, removal of excess cholesterol from.
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