What Is The Main Function Of Cholesterol – The importance of biologically active lipid mediators, prostanoids, leukotrienes and specialized proresolving mediators in the regulation of inflammation is well established. Although the importance of cholesterol in the context of atherosclerosis is also widely recognized, the role of cholesterol and its biosynthetic precursors in inflammatory processes is less well characterized. In this mini-review, we summarize the current understanding of the inflammatory regulatory properties of cholesterol and related biosynthetic intermediates, considering the implications of different subcellular distributions. Finally, we discuss the inflammatory regulatory effects of cholesterol homeostasis in the context of SARS-CoV-2 infections.

The high frequency of hypercholesterolemia, i.e., pathological elevation of plasma cholesterol level, is of great concern, since the simultaneous elevation of low-density lipoprotein (LDL) cholesterol is a major risk factor for the development of cardiovascular diseases such as atherosclerosis. Tsao et al., 2022). In atherosclerosis, LDL-cholesterol accumulates in the arterial intima. When macrophages take up excessive amounts of modified, for example oxidized, LDL-cholesterol, the latter develop a highly activated foam cell phenotype, thereby contributing to the inflammatory nature of atherosclerosis (Choudhury et al., 2005). . Thus, the use of cholesterol-lowering therapeutics, especially statins, which are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, has increased significantly (Salami et al., 2017). The fact that, when intracellular cholesterol production is inhibited, cells are able to cover their cholesterol needs by extracting cholesterol from plasma (Gui et al., 2022) highlights the importance of maintaining intracellular cholesterol levels within a narrow, physiological range. Cholesterol functions as a solvent in cell membranes and as a precursor for various products (eg, steroids, bile acids, vitamin D) (Tabas, 2002). Equally important, cells have developed efficient means to export cholesterol to avoid toxicity due to excess cholesterol (Song et al., 2021). As a side note, high cholesterol concentrations also play an important role in the tumor microenvironment, where they not only support tumor cell proliferation, but also suppress anti-tumor immunity. For details on the role of cholesterol homeostasis in tumor immunity, see (Halimi and Farjadian, 2022).

What Is The Main Function Of Cholesterol

With the recent emergence of the concept of immunometabolism (Mathis and Schoelson, 2011), there has been increasing attention to the tight integration of metabolic processes with immune responses, and intracellular cholesterol dynamics and the equally important cholesterol biosynthetic flux in immune regulation. suggested that it will have an impact. characteristics (Fessler, 2016; O’Hagan et al., 2022). In this review, we provide a brief overview of the inflammatory regulatory functions of various cholesterol biosynthesis intermediates and discuss the implications in the context of SARS-CoV-2.

Vldl And Ldl Metabolism

All mammalian cells have the same mechanisms for regulating their cholesterol levels through a dynamic interplay between their consumption.

Synthesis, storage and export. Cells obtain cholesterol from the plasma, where it is transported mainly wrapped in LDL particles,

LDL receptor (LDLR)-mediated endocytosis (Brown and Goldstein, 1986). After release from LDL particles in the endo-lysosomal compartment, cholesterol is distributed to the intracellular endoplasmic reticulum (ER) or plasma membrane by Niemann-Pick type C (NPC) 1 and 2 proteins (Pfeffer, 2019). Also, cells can

It synthesizes cholesterol in a tightly regulated cascade involving more than 20 enzymes within three subcellular compartments (cytoplasm, ER, and peroxisomes) to meet its cholesterol needs (Charles et al., 2020). Due to its toxic properties, excess free intracellular cholesterol is esterified by acyl coenzyme A:cholesterol acyltransferase (ACAT) and stored in lipid droplets or exported.

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The delicate cholesterol balance is mainly controlled by two opposing transcription factors: Sterol-responsive element-binding protein 2 (SREBP2), which is transported from the ER to the Golgi by SREBP cleavage-activating protein (SCAP) in response to cholesterol depletion in the ER. , where it is cleaved by site 1 protease (S1P) and S2P. The N-terminal transcription factor domain then localizes to the nucleus and facilitates the expression of target genes important for cholesterol biosynthesis and import (Sakai et al., 1996). Conversely, under high cholesterol conditions, SREBP2 is retained in the ER, and oxysterols, the direct precursors of cholesterol, or desmosterol, activate the liver X receptor (LXRα/β), which then induces genes that reduce cholesterol uptake and promote cholesterol export (Janowski et al., 1996). ; Yang et al., 2006) (Fig. 1). For more information, we refer readers to the following comprehensive review (Luo et al., 2020).

FIGURE 1. Cholesterol homeostasis and regulation of inflammation. 1. Uptake: Cholesterol is taken up bound to low-density lipoprotein (LDL) particles.

LDL receptor (LDL-R)-mediated endocytosis is released from LDL by fusion of endosomes with lysosomes and distributed to the endoplasmic reticulum (ER) or plasma membrane by Niemann-Pick type C (NPC) proteins. 2. Biosynthesis: cholesterol is synthesized and converted from acetyl-CoA in the cytoplasm.

In the ER, mevalonate is processed into 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA), which is further processed in peroxisomes into the isoprenoids farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which can also be produced from the GGPP-precursor. geranylgeraniol (GGOH). In the ER, two FPP molecules condense to squalene, which is recycled to lanosterol in a multistep process, which is then metabolized to desmosterol and 7-dehydrocholesterol (7-DHC) in parallel Bloch and Kandutsch-Russel (K-R) pathways. , in turn, both are direct precursors of cholesterol. ER cholesterol levels are sensed by SREBP cleavage-activating protein (SCAP) and insulin-inducible gene (INSIG)-related sterol-responsive element-binding protein 2 (SREBP2) in the ER. Low ER cholesterol levels induce translocation of SCAP-bound SREBP2 to the Golgi, where it undergoes cleavage-dependent activation. The N-terminal SREBP2 fragment functions as a transcription factor for cholesterol biosynthesis enzymes and LDL-R, among others. 3. Efflux: Excess cholesterol in the ER is esterified by acyl coenzyme A:cholesterol acyltransferase (ACAT) and then stored in lipid droplets or exported.

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ATP-binding cassette A1 (ABCA1) or ABCG1 and is loaded onto high-density lipoprotein (HDL) and apolipoprotein A-I (apoA-I) for retrograde transport to the liver. Elevated oxysterol and desmosterol levels further activate the transcription factor liver X receptor (LXR) to increase the expression of cholesterol exporters.

Cholesterol homeostasis and immune responses are intimately linked in a bidirectional manner. As this mini-review focuses on the effects of cholesterol (and cholesterol precursors) on inflammatory responses in innate immune cells, we refer readers to excellent reviews for detailed information on the reprogramming of cholesterol metabolism in infections (Robertson et al. Ghazal, 2016; Lee and Bensinger, 2022).

A general reduction in cholesterol biosynthetic flux has been described to induce spontaneous induction of interferon-stimulated genes (ISGs) (York et al., 2015) and enhanced antiviral responses to infections (Xiao et al., 2020). . In addition, SREBP2 has been shown to directly bind and activate the transcription of ISGs and subsequent pro-inflammatory genes (Kusnadi et al., 2019). Regardless of its SREBP2-activating function, the cholesterol sensor SCAP also translocates interferon-regulatory factor 3 (IRF3) from the ER to Golgi-localized stimulator of interferon genes (STING), linking cholesterol homeostasis to inflammation and thereby was observed to facilitate ISG induction. after infection (Chen et al., 2016) and by activating the pyrin domain of the NLR family involving the inflammasome 3 (NLRP3) (Guo et al., 2018). In the following sections, we summarize the current understanding of the immunoregulatory functions of cholesterol and related biosynthetic intermediates.

As exemplified by the pro-inflammatory nature of foam cells loaded with modified LDL-cholesterol in atherosclerosis (Tall and Yvan-Charvet, 2015), high cholesterol levels in innate immune cells are generally associated with anti-inflammatory functions. . Along these lines, cholesterol crystals are recognized as inducers of the NLRP3 inflammasome in macrophages in atherosclerosis (Duewell et al., 2010).

Abnormal Brain Cholesterol Homeostasis In Alzheimer’s Disease—a Targeted Metabolomic And Transcriptomic Study

In addition to total cellular cholesterol levels, its intracellular distribution appears to be critical for inflammatory functions. For example, the unperturbed trafficking of cholesterol to the ER is required for the activation and consequent expression of nuclear factor-kappa-light chain enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling. The pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in response to excess free cholesterol (Li et al., 2005). Similarly, lowering ER cholesterol levels by NPC1 inhibition or statin treatment abrogated NLRP3 inflammasome activation, resulting in significantly reduced IL-1β and IL-18 secretion. Although activation of the NLRP3 inflammasome required complete translocation of cholesterol to the ER, the DNA-sensing poly(deoxydenylic-deoxythymidyl) acid (poly(dA:dT)) absent in the melanoma 2 (AIM2) inflammasome ) was not affected by the collection and activation of the city. in cholesterol distribution (de la Roche et al., 2018). Interestingly, the increased accumulation of cholesterol in the ER caused by the experimental loss of cholesterol-25-hydroxylase (Ch25h) led to mitochondrial (mt) dysfunction and mtDNA release, thereby leading to the activation of the AIM2 inflammasome in response to lipopolysaccharide. . LPS)-stimulation (Dang et al., 2017).

In addition, cholesterol, like other membrane lipids, affects the localization of various pattern recognition receptors (PRRs) to specific organelles and/or membrane microdomains known as lipid rafts, which is again important for the regulation of their activity. For further information, readers are referred to comprehensive reviews (Ruysschaert and Lonez, 2015; Köberlin et al., 2016). Therefore, it is not surprising that changes in intracellular cholesterol distribution are associated with altered toll-like receptor (TLR) sensitivity. For example, cholesterol loading on plasma membranes by cholesterol complexed with methyl-β-cyclodextrin (CD) is sufficient to initiate spontaneous TLR4 signaling in murine macrophages. Conversely, increased cholesterol accumulation in the endosome achieved by co-addition of acetylated LDL-cholesterol and inhibition of NPC1 induced TLR3 responses ( Sun et al., 2009 ). A recent study showed that the accumulation of free cholesterol in endosomes and lysosomes upon TLR4 activation is essential for efficient myeloid differentiation.

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