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What Role Does Cholesterol Play In The Cell Membrane

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Cholesterol Access In Cellular Membranes Controls Hedgehog Signaling

By María Aguilar-Ballester María Aguilar-Ballester Scilit Preprints.org Google Scholar View Publications 1 , Andrea Herrero-Cervera Andrea Herrero-Cervera Scilit Preprints.org Google Scholar View Publications 1 , Ángela Vinué Ángela Vinué Scilit Preprints.org Google Scholar View Publications 1 , Sergio Martínez-Hervás Sergio Martínez-Hervás Scilit Preprints.org Google Scholar View Publications 1, 2, 3 and Herminia González-Navarro Herminia González-Navarro Scilit Preprints.org Google Scholar View Publications 1, 3, 4, *

Received: 15 June 2020 / Revised: 29 June 2020 / Accepted: 2 July 2020 / Published: 7 July 2020

Cholesterol, the most important sterol in mammals, helps maintain plasma membrane fluidity and is a precursor to bile acids, oxysterols, and steroid hormones. Cholesterol in the body comes from food or can be synthesized de novo. Cholesterol homeostasis is primarily regulated by the liver, where cholesterol is packaged into lipoproteins for transport through a tightly regulated process. Changes in the cholesterol level of circulating lipoproteins lead to the development of atherosclerosis, the initiator of which is the accumulation of modified lipoproteins in the subendothelial space; it causes significant changes in the differentiation and function of immune cells. In addition to damage, cholesterol levels also play important roles in immune cells, such as monocyte priming, neutrophil activation, hematopoietic stem cell mobilization, and enhanced T cell production. In addition, changes in intracellular metabolic enzymes or cholesterol transporters in immune cells affect their signaling and phenotype differentiation, which may influence the development of atherosclerosis. In this review, we describe the main regulatory pathways and mechanisms of cholesterol metabolism and how they affect the generation, proliferation, activation and signaling of immune cells in the context of atherosclerosis.

Cholesterol is the major sterol in mammals and plays a key role in the plasma membrane, where it is responsible for modulating membrane fluidity, permeability, and signaling [ 1 ]. It is also found in small amounts in the endoplasmic reticulum (ER) membrane, where it is important for its metabolic regulation [2]. Cholesterol is also involved in cell proliferation and embryonic signaling and is a precursor to bile acids, oxysterols, and all steroid hormones.

Regulation Of Membrane Protein Structure And Function By Their Lipid Nano Environment

Blood cholesterol levels are determined by dietary cholesterol intake and cholesterol synthesized de novo from acetyl-coenzyme A (acetyl-CoA). Cholesterol homeostasis is tightly regulated by the liver, which controls the assembly, secretion, and catabolism of lipoproteins [1]. Altered cholesterol metabolism and regulation of its circulating levels have a major impact on atherosclerosis, a chronic inflammatory disease. Given that cholesterol is required for all cell membranes, genes involved in cholesterol biosynthesis, regulatory pathways, transport, and receptors are ubiquitous in all cell types, including inflammatory and immune cells. Recent studies have shown that the progression of atherosclerosis is influenced not only by circulating cholesterol levels, but also by cholesterol content and metabolism in immune cells, even in the absence of changes in systemic cholesterol levels or defects in cholesterol transport.

In this review, we summarize cholesterol metabolism and transport and their effects on immune cell function, production, and activity.

In the following sections, we provide an overview of the major and state-of-the-art pathways and key modulators of intracellular cholesterol metabolism and circulating cholesterol levels, which are also summarized in Figure 1 and Figure 2 .

In the intestinal lumen, cholesterol binds to bile salt micelles and is transported by Niemann–Pick C1-Like 1 (NPC1L1) across the enterocyte brush border membrane via clathrin-mediated endocytosis [1, 2, 3] (Fig. 1). NPC1L1 is a cholesterol-sensitive receptor that translocates from the endocytic recycling compartment to the membrane [3]. During this process, ras-associated binding protein (RAB)11a bound to NPC1L1 is replaced by cell division control protein (CDC)42, which activates actin polymerization promoters that transport NPC1L1 back to the cell surface. Under cholesterol depletion, NPC1L1 is also regulated by the transcription factor sterol regulatory element-binding protein 2 (SREBP2) and by lysosomal and ubiquitin-proteasomal degradation [ 3 , 4 ]. Inside the enterocytes, cholesterol is re-esterified by the enzyme acetyl-CoA (Ac-CoA) acetyltransferase 2 (ACAT2) [5] and assembled into chylomicrons, a triglyceride-rich lipoprotein type with a cholesteryl ester-rich core and a single protein molecule of apolipoprotein B (ApoB) 48 on its surface. These newborn chylomicrons are released into the intercellular space, migrate to the lamina propria, and enter the lacteal vessels of the lymphatic system for transport through the portal vein to the liver or into the circulation through the thoracic duct [2] (Fig. 1).

Harnessing The Reverse Cholesterol Transport Pathway To Favor Differentiation Of Monocyte Derived Apcs And Antitumor Responses

Dietary cholesterol is digested, solubilized in bile salt micelles in the intestine, and taken up in the apical region of enterocytes by NPC1L1, where it is assembled into nascent chylomicrons. Chylomicrons will be transported to the liver via the portal vein of the enterohepatic circulation, although they may enter the circulation via the thoracic duct. Cholesterol can also be endogenously synthesized from Ac-CoA. In the liver, it is collected into very low-density lipoproteins (VLDL), which are secreted into the bloodstream. Triglycerides in chylomicrons and LDL are hydrolyzed by lipoprotein lipase (LPL), increasing their density and forming chylomicron remnants and low-density lipoprotein (LDL) particles, which can be further catabolized by hepatic lipase (HL). HDL and LDL are also enriched with cholesterol by cholesterol transfer protein (CETP), which transfers cholesterol esters from high-density lipoprotein (HDL). The resulting chylomicron remnants are absorbed by the liver, and the components enter the lipoprotein package. LDL delivers cholesterol via an endocytic process mediated by the LDL receptor (LDLr) to most tissues. In the subendothelial space, LDL undergoes various modifications, such as oxidation, acetylation or aggregation to form modified LDL (mLDL), which are taken up by macrophages via the scavenger receptor (SR)-A, cluster of differentiation (CD)36. , and low-density lipoprotein receptor-1 (LOX-1) to become foam cells. Excess cholesterol undergoes an efflux process mediated by adenosine triphosphate-binding cassette transporter A1 (ABCA1) and adenosine triphosphate-binding cassette transporter G1 (ABCG1), which interact with the cholesterol acceptor nascent discoidal lipid apolipoprotein A (ApoA)-I. bad HDL. Mature, spherical, lipid-enriched HDL is returned by reverse cholesterol transport to the liver, where it delivers cholesterol through the receptor class B type 1 (SRBI). Cholesterol is stored in the liver and can be used for bile salt synthesis in the farnesoid X receptor (FXR)-regulated pathway by the limiting enzyme cytochrome P450 family 7 subfamily A member 1 (CYP7A1). Cholesterol can also be secreted into the gallbladder by adenosine triphosphate-binding cassette transporter G5/G8 (ABCG5/G8) along with bile salts secreted by adenosine triphosphate-binding cassette subfamily B 11 (ABCB11) until they are secreted into the intestine for excretion with feces Reabsorption of NPC1L1 on the apical side of enterocytes may incorporate cholesterol back into chylomicrons. For intracellular storage, cholesterol is esterified by ACAT2 in hepatocytes and ACAT1 in the remaining cell types.

Depletion of cellular cholesterol activates the biosynthesis of endogenous cholesterol from Ac-CoA molecules in an energetically expensive anabolic pathway regulated by SREBP2 and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoAR). SREBP2 is synthesized as an ER-anchored precursor that is translocated with SREBP cleavage-activating protein (SCAP) to the Golgi apparatus for activation by site 1 (SP1) and SP2 protease cleavage. Insulin-induced gene 1 (INSIG1) and INSIG2 proteins preserve the interaction of SREBP–SCAP dimers when the sterol-sensitive domains (SSD) of SCAP detect ER membrane cholesterol above 5 mol.% of total lipids [3, 4, 6, 7] (Fig. 2).

Activated nuclear SREBP binds to sterol regulatory element (SRE) sequences to activate transcription in target genes, including self; its synergistic inducers of nuclear transcription factor Y subunit alpha (NF-Y) and SP1; its FOXO3 inhibitor; and HMG-CoAR, an ER glycoprotein that converts HMG-CoA to mevalonate and is inhibited by nonsterol isoprenoids [3]. High cholesterol reduces HMG-CoAR activity via INSIG1 and INSIG2, which bind to HMG-CoAR via ubiquitin ligases for degradation via different pathways [8]

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