Abstract
Cholesterol, the most important sterol in mammals, helps maintain plasma membrane fluidity and is a precursor of bile acids, oxysterols, and steroid hormones. Cholesterol in the body is obtained from the diet or can be de novo synthetized. Cholesterol homeostasis is mainly regulated by the liver, where cholesterol is packed in lipoproteins for transport through a tightly regulated process. Changes in circulating lipoprotein cholesterol levels lead to atherosclerosis development, which is initiated by an accumulation of modified lipoproteins in the subendothelial space; this induces significant changes in immune cell differentiation and function. Beyond lesions, 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 cholesterol intracellular metabolic enzymes or transporters in immune cells affect their signaling and phenotype differentiation, which can impact on atherosclerosis development. In this review, we describe the main regulatory pathways and mechanisms of cholesterol metabolism and how these affect immune cell generation, proliferation, activation, and signaling in the context of atherosclerosis.
Highlights
Cholesterol is the main sterol in mammals and has a key role in the plasma membrane where it is responsible for modulating membrane fluidity, permeability, and signaling [1]
high-fat diet (HFD)-fed Abcg1-/- and Abca1-/-Abcg1-/- mice displayed granulocyte-colony stimulating factor (G-CSF)-induced neutrophilia, which was attributed to facilitated toll-like receptor (TLR)4/ myeloid differentiation primary response (MyD)88 signalling and cytokine production in macrophages caused by cholesterol plasma membrane accumulation [27]
hematopoietic progenitor/stem cells (HPSC) was shown to differentiate from hemogenic endothelium through trans-activation of notch embryonic signaling by sterol regulatory element-binding protein 2protein (SREBP2), which attributes a major role to SREBP2 in this cellular type in hematopoiesis rather than cholesterol biosynthesis
Summary
Cholesterol is the main sterol in mammals and has a key role in the plasma membrane where it is responsible for modulating membrane fluidity, permeability, and signaling [1] It is found in the endoplasmic reticulum (ER) membrane in small amounts where it is essential for its metabolic regulation [2]. Recent studies have indicated that atherosclerosis progression is affected by circulating cholesterol levels and by cholesterol content and metabolism within immune cells, even in the absence of changes in systemic cholesterol levels or defects in cholesterol transport. Nutrients 2020, 12, 2021 content and metabolism within immune cells, even in the absence of changes in systemic cholesterol levels or defects in cholesterol transport.
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