Impact of Cholesterol Metabolism in Immune Cell Function and Atherosclerosis

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.

Keywords: atherosclerosis; cholesterol; hematopoiesis; immune cells; inflammation; metabolism.

Figure 1

Cholesterol and lipoprotein metabolism.

Figure 2

Cholesterol and bile acid biosynthesis. (A) In conditions of cholesterol depletion, the sterol regulatory element-binding protein 2 (SREBP2)–SREBP cleavage activating protein (SCAP) complex in the ER is transported to the Golgi apparatus where it is sequentially cleaved by site 1 protease (SP1) and SP2 at different sites to become active. Active nuclear (n)SREBP2 enters into the nucleus and binds to sterol regulatory element (SRE) sequences of target genes to induce the expression of genes involved in cholesterol synthesis such as the rate-limiting cholesterol synthesis enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (HMG-CoAR). De novo synthetized cholesterol is stored or assembled in very low density lipoproteins (VLDL) in the Golgi apparatus for secretion into the circulation. (B) When ER membrane cholesterol exceeds 5% mol of the total lipids, sterol-sensing domains (SSD) in SCAP undergo a conformational change and the complex binds to insulin-induced gene 1 (INSIG1) or INSIG2, remaining inactive. Meanwhile, HMG-CoAR also binds to INSIG1 or INSIG2 for ubiquitilation and degradation, or it is inactivated by phosphorylation. (C) Cholesterol enters into the hepatocyte by low-density lipoprotein (LDL) receptor (LDLr) or through scavenger receptor class B type 1 (SRBI) by the delivery of high-density lipoprotein (HDL) reverse cholesterol transport. In the liver, it is stored as cholesterol ester after being esterified by acetyl coenzyme A (Ac-CoA) acetyltransferase 2 (ACAT2). It can also be used to synthetize bile acids in the biosynthetic metabolic pathway with the cytochrome P450 family 7 subfamily A member 1 (CYP7A1) enzyme as a rate-limiting factor. Bile acids will be secreted into the gallbladder as bile salts by adenosine triphosphate-binding cassette subfamily B member 11 (ABCB11) transporter. Cholesterol excess is also effluxed by adenosine triphosphate-binding cassette transporter G5/G8 (ABCG5/G8) into the gallbladder for secretion into the intestine.

Figure 3

Impact of cholesterol on immune cells. (A) Neutrophil activation is induced under hypercholesterolemic conditions, in which oxidized (ox)LDL and reactive oxidant species (ROS) levels increase, while cholesterol efflux genes such as liver X receptor (LXR) and transporters adenosine triphosphate-binding cassette transporter A1 (ABCA1) and adenosine triphosphate-binding cassette transporter G1 (ABCG1) are downregulated. Activated neutrophils contribute to atherosclerotic plaque formation and instability by NETosis, a process consisting of the release of neutrophil extracellular traps (NETs) and secretion of lysozyme, myeloperoxidase (MPO), and neutrophil elastase (NE), which contributes to endothelial injury. (B) Hypercholesterolemia induces macrophage activation, differentiation, and function in atheroma lesions. Monocyte-derived macrophages accumulate cholesterol and form foam cells through the uptake of lipoproteins (chylomicron remnants, VLDL, LDL, oxLDL, and apolipoprotein (a) (Lp(a)), thus forming atherosclerotic plaque. In the atheroma plaque environment, macrophages acquire a proinflammatory phenotype as intracellular cholesterol accumulation activates inflammasome (NLRP3), enhancing the production of cytokines and ROS. ApoB lipoproteins might induce apoptosis and necrosis of stressed macrophages, facilitating the generation of vulnerable plaques. Anti-inflammatory macrophages, with a proresolving phenotype, secrete collagen; induce tissue repair; and enhance macrophage cholesterol efflux, efferocytosis, and reverse cholesterol transport. A third type of macrophage called M(ox) has been described, which displays decreased phagocytic activity and promotes the overexpression of genes controlled by the transcription nuclear factor erythroid 2–related factor (NRF)2. (C) Enrichment of cholesterol in lipid rafts in T cells facilitates the clustering of T cell receptor (TCR) signaling complexes and hence immune synapse. These processes lead to T cell activation and proliferation, T helper (Th)17 and Th1 differentiation, and a decrease in the regulatory T (Treg) population. To ensure T cell expansion, SREBP- and HMG-CoAR-mediated cholesterol synthesis is also upregulated, while LXR-dependent efflux pathways are repressed. (D) Cholesterol enrichment of lipid rafts in hematopoietic progenitor/stem cells (HPSC), caused by hypercholesterolemia and/or a defective cholesterol efflux, affects HPSC quiescence, proliferation, migration, and hematopoiesis. Activated SREBP2-signaling increases cholesterol levels and affects HPSC differentiation. Decreased LXR-dependent cholesterol efflux promotes proliferation of Lin-Sca+cKit+ (LSK+) HPSC population and granulocyte-colony stimulating factor (G-CSF)-mediated granulocyte production, enhancing circulating monocytes and neutrophils. High cholesterol levels also downregulate TET-1 gene expression in HPSC, which impairs its stem cell capacity.