What Is The Function Of Cholesterol In The Body – Cholesterol is a lipid molecule that plays an important role in several biological processes, both physiological and pathological. It is an essential component of cell membranes, and is essential for the biosynthesis, integrity, and functions of biological membranes, including membrane trafficking and signaling. In addition, cholesterol is the main lipid component of lipid rafts, a type of lipid-based material that controls the organization and function of many cellular signaling processes, including those associated with cancer, such as tumor growth, adhesion, migration, invasion, and apoptosis. Given the importance of cholesterol metabolism, its homeostasis is carefully controlled at each stage: intake, synthesis, export, metabolism, and storage. Changes in this homeostatic balance are known to be associated with cardiovascular disease and atherosclerosis, but more and more evidence links this to an increased risk of cancer. Although there is conflicting evidence on the role of cholesterol in the development of cancer, many studies show that disturbances in cholesterol homeostasis can lead to the development of cancer. This review aims to discuss the current understanding of cholesterol homeostasis in normal and cancerous cells, and summarize the findings from recent medical and clinical studies that have investigated the role of participants in the regulation of cholesterol and lipid rafts, which may represent therapeutic incentives. .

Cholesterol is the primary lipid molecule that plays an important role in several biological, physiological and physiological processes (Maxfield and Tabas, 2005).

What Is The Function Of Cholesterol In The Body

What Is The Function Of Cholesterol In The Body

Cholesterol, in addition to being an important component of cell membranes, is essential for their biological production, and is essential for maintaining the integrity and functions of natural membranes, including endocytosis, membrane trafficking, and signaling (Maxfield and Tabas, 2005; Yamauchi and Rogers, 2018). . Inside the cell, cholesterol, distributed differently among the organelles, modifies the immune system, and represents the precursor of hormones such as sex hormones and vitamin D (Mollinedo and Gajate, 2020; Figure 1).

Smooth Endoplasmic Reticulum (ser)

Recently, cholesterol has taken a major role in cancer research because of its potential for treatment and prevention. However, the role of cholesterol in oncogenesis is still controversial (DuBroff and de Lorgeril, 2015). Most of the literature also reported a conflicting role of cholesterol depending on the type of tumor (Ding et al., 2019). High cholesterol is associated with breast, colon, rectal, prostatic, and testicular cancer (Llaverias et al., 2011; Pelton et al., 2012; Murai, 2015; Radisauskas et al., 2016), while other studies that expected to show an inverse association with colon and prostate cancer (Asano et al., 2008; Heir et al., 2016). This review aims to discuss the current findings of cholesterol homeostasis, critically analyze the most recent medical studies that investigate the role of those involved in the cholesterol biosynthetic pathway, and the formation of cholesterol fatty acids in the cancer field.

Cholesterol is produced through an enzymatic pathway, the mevalonate pathway, which requires the participation of various enzymes found on the endoplasmic reticulum (ER) membrane. Briefly, combining three molecules of acetyl-CoA results in the production of one molecule of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). The latter, by the action of HMG-CoA reductase (HMGCR), is converted to mevalonate, then converted to squalene (SQL), and finally to cholesterol through several processes (Figure 2). Food can also be a source of cholesterol. Instead, the Niemann-Pick C1-like 1 (NPC1L1) protein located on the intestinal membrane of enterocytes, is responsible for the absorption of cholesterol, which is released as chylomicrons, small triglyceride particles, and is absorbed. and liver (Altmann et al., 2004; Luo et al., 2020).

Figure 2. Cholesterol biosynthesis pathway and principal inhibitors. Starting from three molecules of acetyl-coenzyme A (CoA), cholesterol is produced 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, inhibitors of sterol regulating binding protein (SREBP) that inhibit the transcription of cholesterol biosynthesis genes; are bisphosphonates that act downstream of statins by inhibiting farnesyl pyrophosphate synthase and the subsequent reduction of farnesyl pyrophosphate and geranylgeranyl pyrophosphate. This pathway of cholesterol biosynthesis is also controlled by farnesyl transferase inhibitors.

Cholesterol is produced mainly in the liver and enters the bloodstream as low-density lipoproteins (VLDLs). In the blood, VLDLs are converted to low-density lipoproteins (LDLs), transported to the blood cells and blood (Ikonen, 2008; Goldstein and Brown, 2009). LDLs enter cells through receptor (LDLR)-mediated endocytosis and are transported to lysosomes where they are incorporated into free cholesterol molecules, which are transported to cell membranes to carry out several functions (Brown and Goldstein, 1986; Ikonen, 2008). ; Maxfield and van Meer, 2010; Kuzu et al., 2016).

Functions Of Cholesterol

The mevalonate pathway is tightly regulated by transcriptional and translational pathways that can respond to physiological signals. Cholesterol biosynthesis is controlled by four main players: (1) sterol regulatory element-binding protein 2 (SREBP2), which functions negatively (Sato, 2010), (2) liver X Receptors (LXRs), (3) HMGCR. , and (4) squalene epoxidase (SQLE). HMGCR and SQLE are rate-limiting enzymes, which can regulate cholesterol biosynthesis, making it more expensive. When intracellular ATP levels are low, 5’adenosine monophosphate-activated protein kinase (AMPK) phosphorylates HMGCR to inhibit its activity (Loh et al., 2019). Also, HMGCR is affected by the presence of LDL in the medium; In fact, during LDL starvation, the activity of HMGCR increases, while it decreases significantly when LDL is added. On the other hand, after cholesterol has finished its function, its residues are exported via ATP-binding cassette (ABC) subfamily A member 1 (ABCA1) or ABC subfamily G member 1 (ABCG1) to lipid-poor apolipoprotein A-I (ApoA-I. ), thus producing high-density lipoproteins (HDLs) (Gelissen et al., 2006; Lorenzi et al., 2008; Daniil et al., 2013; Phillips, 2014). ABCA1 transcription is regulated by nuclear LXRs when the intracellular cholesterol level is high (Wang et al., 2008; Ouvrier et al., 2009; Kuzu et al., 2016). CoA:cholesteryl acyltransferase 1 (ACAT1) converts excess cholesterol into non-toxic substances, such as cholesteryl esters (CEs), which are stored as lipid droplets and are used to synthesize large plasma lipoproteins (chylomicrons, VLDLs, LDLs, and HDLs ). ). HDLs are transported from peripheral tissues back to the liver and intestines, to restore or remove cholesterol, and go to the steroidogenic organs, where cholesterol is used to make steroid hormones (Chang et al., 2009; Luo et al., 2020).

Recent research on microRNAs (miRNAs), a group of non-coding RNAs, has revealed their role in cholesterol homeostasis by modulating some key parameters of the system (Wagschal et al., 2015). For example, under low sterol conditions, high transcription of miR-33a is required to regulate cholesterol secretion and HDL metabolism through ABCA1 inhibition (Wagschal et al., 2015). In contrast, miR-223 regulates cholesterol levels by inhibiting its production and regulating cholesterol secretion by increasing ABCA1 levels (Vickers et al., 2014). miRNA-122, which is mainly found in hepatocytes, when inhibited it significantly lowers blood cholesterol (Rotllan and Fernandez-Hernando, 2012). miR-27a has been shown to regulate the level of HMGCR either by a posttranslational block or by mRNA degradation (Khan et al., 2020). Interestingly, some miRNAs have been found by meta-analysis to be associated with cholesterol-lipoprotein changes, such as miR-128-1, miR-148a, miR-130b, and miR-301b. These miRNAs were able to increase circulating cholesterol by regulating the expression levels of LDLR and ABCA1 (Wagschal et al., 2015).

These data indicate the involvement of miRNAs in the regulation of lipid metabolism, and emphasize their possible contribution to the regulation of lipid metabolism after perturbation.

What Is The Function Of Cholesterol In The Body

Given the importance of cholesterol metabolism, its cellular homeostasis is carefully controlled at each stage: import, synthesis, export, export, and esterification (Ikonen, 2008). Sterol regulatory element-binding protein 2 (SREBF2) and LXRs act as regulators of cholesterol homeostasis (Ikonen, 2008). In the ER, only cholesterol controls its homeostasis. Low cholesterol levels induce the translocation of SREBP2 to the nucleus, which promotes the activation of genes involved in the biosynthesis (eg, HMGCR) and uptake (eg, LDLR) of cholesterol (Ikonen, 2008). High cholesterol levels inhibit cholesterol synthesis and regulate its transport through the activation of LXRs and oxysterols, oxidized derivatives of cholesterol (Wang et al., 2008; Kuzu et al., 2016). Recent studies on LNCaP prostate cancer cells revealed 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 caused cell arrest and promoted apoptosis (Pommier et al., 2010). The relationship between LXRs, cholesterol, and prostate cancer suggests that LXRs have the potential to one day target this tumor.

Lipoproteins, Cholesterol, And Diet Explained

During the biosynthesis of cholesterol, depending on the type of tissue, various intermediate sterols are produced, such as cholesteryl ester, oxysterols, bile acids, cholecalciferol/vitamin D, and various steroid hormones. Both sterols have important physiological functions in cells and tissues (Simons and Ikonen, 2000). Some cholesterol metabolites can also promote the development and transformation of some types of cancer (Lin et al., 2013; McDonnell et al., 2014; Baek et al., 2017).

In healthy conditions, high cholesterol is caused by a conflict between synthesis, absorption from external sources, removal of residual cholesterol from

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