What Is The Purpose Of Cholesterol In The Body – Cholesterol is a lipid molecule that plays an essential role in several biological, physiological and pathological processes. It is an essential structural component of cell membranes, and is essential for the biosynthesis, integrity and functions of biological membranes, including membrane trafficking and signaling. Moreover, cholesterol is the main lipid component of lipid rafts, a kind of lipid-based structures that regulate the assembly and function of many cell signaling pathways, including those associated with cancer, such as tumor cell growth, adhesion, migration, invasion, and apoptosis. Given the importance of cholesterol metabolism, its homeostasis is strictly regulated at each stage: import, synthesis, export, metabolism and storage. Changes in this homeostatic balance are known to be associated with cardiovascular disease and atherosclerosis, but increasing evidence links these behaviors to increased cancer risk. Although there is conflicting evidence regarding the role of cholesterol in cancer development, most studies consistently indicate that dysregulation of cholesterol homeostasis may lead to cancer development. This review aims to discuss the current understanding of cholesterol homeostasis in normal and cancerous cells, summarizing key findings from recent preclinical and clinical studies that have investigated the role of key players in cholesterol regulation and lipid raft organization, which may represent promising therapeutic targets. .
Cholesterol is a primary lipid molecule that plays an essential role in several biological processes, both at the physiological and pathological levels (Maxfield and Tabas, 2005).
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What Is The Purpose Of Cholesterol In The Body
Cholesterol, in addition to being an important component of cell membranes, is fundamental to their biogenesis, and is necessary for maintaining 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 the organelles, regulates the immune system, and represents a precursor of hormones such as sex hormones and vitamin D (Mollinedo and Gajate, 2020; Figure 1).
What Is The Difference Between Good And Bad Cholesterol?
Recently, cholesterol has played a central role in cancer research because of its potential therapeutic implications in both prevention and treatment. However, the role of cholesterol in oncogenesis is still under debate (DuBroff and de Lorgeril, 2015). Literature data reported a conflicting role of cholesterol depending on the tumor type (Ding et al., 2019). Excess cholesterol is associated with breast, colon, rectal, prostate and testicular cancer (Llaverias et al., 2011; Pelton et al., 2012; Murai, 2015; Radisauskas et al., 2016), while some prospective cohort studies have shown an inverse association in cancer the stomach and prostate (Asano et al., 2008; Heir et al., 2016). This review aims to discuss the current knowledge of cholesterol homeostasis, while critically analyzing the most recent preclinical and clinical studies investigating the role of the main players in the cholesterol biosynthetic pathway, and the lipid rafts of the cholesterol-based membrane structure in cancer.
Cholesterol is produced through a cascade of enzymatic reactions, namely, the mevalonate pathway, which requires the participation of various enzymes located on the membranes of the endoplasmic reticulum (ER). Briefly, the combination of three acetyl-CoA molecules leads to the formation of one 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) molecule. The latter, by the action of HMG-CoA reductase (HMGCR), is converted to mevalonate, in turn to squalene (SQL), and finally to cholesterol through several reactions (Figure 2). Food can also be a source of cholesterol. In fact, the Niemann-Pick protein C1-like 1 (NPC1L1), present on the membrane of enterocytes in the intestines, is responsible for the absorption of cholesterol, which is released as chylomicrons, fat particles rich in triglycerides, and absorbed. by the liver (Altmann et al., 2004; Luo et al., 2020).
Figure 2. Cholesterol biosynthesis pathway and main inhibitors. Starting from three molecules of acetyl-coenzyme A (CoA), cholesterol is synthesized in more than 20 enzymatic steps. 3-Hydroxy-3-methylglutaryl-CoReductase (HMGCR) and squalene epoxidase (SQLE) act as rate-limiting enzymes. The main inhibitors of cholesterol biosynthesis are statins that inhibit HMGCR, sterol regulatory binding protein (SREBP) inhibitors that inactivate the transcription of cholesterol biosynthesis genes; and bisphosphonates that act downstream of statins and inhibit farnesyl pyrophosphate synthase with a sequential decrease of farnesyl pyrophosphate and geranylgeranyl 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 (VLDL). In the bloodstream, the VLDLs undergo transformation to produce low-density lipoproteins (LDLs), which are transported to peripheral cells by the bloodstream (Ikonen, 2008; Goldstein and Brown, 2009). LDLs enter cells through receptor-mediated endocytosis (LDLR) and are transported to lysosomes where they are hydrolyzed into free cholesterol molecules, which are transported to cell membranes to perform its multiple functions (Brown and Goldstein, 1986; Ikonen, 2008; Maxfield and van Meer, 2010; Kuzu et al. , 2016).
Cholesterol: Understanding Hdl Vs. Ldl
The mevalonate pathway is tightly regulated by transcriptional and translational mechanisms capable of responding to physiological signals. Cholesterol biosynthesis is regulated by four main players: (1) 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 SLE are rate-limiting enzymes, which can regulate cholesterol biosynthesis, the reactions they catalyze are energetically expensive. When intracellular ATP levels are low, 5’adenosine monophosphate-activated protein kinase (AMPK) phosphorylates HMGCR inhibiting its function (Loh et al., 2019). Moreover, HMGCR is affected by the presence of LDL in the medium; In fact, after LDL starvation, HMGCR activity increases, whereas it strongly decreases when LDL is added back. On the other hand, once cholesterol has exhausted its function, its excess is exported via ATP-binding cassette (ABC) subfamily A member 1 (ABCA1) or ABC subfamily G member 1 (ABCG1) to low-fat apolipoprotein A-I (ApoA-I) ). thereby creating high-density lipoproteins (HDLs) (Gelissen et al., 2006; Lorenzi et al., 2008; Daniil et al., 2013; Phillips, 2014). The transcription of ABCA1 is regulated by nuclear LXRs when the intracellular cholesterol level is high (Wang et al., 2008; Ouvrier et al., 2009; Kuzu et al., 2016). The CoA:cholesteryl acyltransferase 1 (ACAT1) converts excess cholesterol into less toxic compounds, such as cholesterol esters (CE), which are stored as lipid droplets and are used to produce the main lipoproteins in the plasma (chylomicrons, VLDLs, LDLs and HDLs). HDL materials from peripheral tissues are then transported back to the liver and intestine, to recycle or eliminate cholesterol, and to steroidogenic organs, where cholesterol is used to create 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 modulating several important components of the system (Wagschal et al., 2015). For example, under conditions of low sterol concentration, higher transcription of miR-33a is required to control cholesterol export and HDL metabolism through ABCA1 inhibition (Wagschal et al., 2015). Conversely, miR-223 regulates the amount of cholesterol by inhibiting its production and improving cholesterol efflux by increasing ABCA1 levels (Vickers et al., 2014). miRNA-122, which is mainly present in hepatocytes, when inhibited significantly suppresses blood cholesterol level (Rotllan and Fernandez-Hernando, 2012). miR-27a has been shown to control HMGCR level by blocking post-translation or by mRNA degradation (Khan et al., 2020). Remarkably, other miRNAs were found by meta-analyses to be associated with changes in cholesterol-lipoprotein trafficking, such as miR-128-1, miR-148a, miR-130b and miR-301b. These miRNAs were able to increase circulating cholesterol by controlling the expression level of LDLR and ABCA1 (Wagschal et al., 2015).
These data indicate the participation of miRNAs in the control of cholesterol metabolism, highlighting how they can contribute to changes in cholesterol levels when they are not regulated.
Given the importance of cholesterol metabolism, its cellular homeostasis is strictly regulated at each step: import, synthesis, export, transport and esterification (Ikonen, 2008). Sterol-binding element-regulatory protein 2 (SREBF2) and LXR act as key regulators of cholesterol homeostasis (Ikonen, 2008). In the ER, cholesterol itself regulates its homeostasis. Low cholesterol levels cause SREBP2 to translocate to the nucleus where it promotes activation of genes involved in the biosynthesis (eg, HMGCR) and uptake (eg, LDLR) of cholesterol (Ikonen, 2008). High cholesterol levels inhibit cholesterol synthesis and facilitate its export through the activation of LXRs by oxysterols, oxidized derivatives of cholesterol (Wang et al., 2008; Kuzu et al., 2016). Recent studies on LNCaP prostate cancer cells highlighted an important protective role of LXRs (Pommier et al., 2010; Fu et al., 2014). In fact, the activation of these transcription factors that regulate cholesterol homeostasis was able to induce cell cycle arrest and promote apoptosis (Pommier et al., 2010). The relationship between LXRs, cholesterol and prostate cancer emphasizes that LXRs have a good chance of being targeted one day in this tumor.
Last Step In The Path Of Ldl Cholesterol From Lysosome To Plasma Membrane To Er Is Governed By Phosphatidylserine
During cholesterol biosynthesis, depending on the type of tissue, various intermediate sterols such as cholesterol esters, oxysterols, bile acids, cholecalciferol/vitamin D and various steroid hormones are formed. All these sterols have important physiological roles in cells and tissues (Simons and Ikonen, 2000). Certain cholesterol metabolites may also contribute to the progression and metastasis of certain types of cancer (Lin et al., 2013; McDonnell et al., 2014; Baek et al., 2017).
Under healthy conditions, the amount of cholesterol is the result of a balance between synthesis, absorption from the extracellular environment, elimination of excess cholesterol from
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