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Lipid homeostasis in macrophages – Implications for atherosclerosis

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Reviews of Physiology Biochemistry and Pharmacology

Part of the book series: Reviews of Physiology, Biochemistry and Pharmacology ((REVIEWS,volume 160))

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Abstract

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In industrialized societies with excess food supply, obesity is an expanding problem. As a result of metabolic overload, besides obesity, insulin resistance, type-2 diabetes, dyslipidemia, hypertension, and atherosclerosis develop, which together make up the metabolic syndrome. The imbalance of lipid uptake, metabolism, and removal in many organs such as the liver, muscle, adipose tissue, vessel wall, and macrophages triggers organ transdifferentiation toward lipid storage phenotypes. Macrophages, foam cells, and osteoclasts in calcifying lesions are a hallmark of atherosclerosis and the metabolic syndrome, and must be regarded as an important therapeutic target. In this review, pathways regulating lipid homeostasis in macrophages are updated. These include lipid influx through different receptor entry pathways, the role of membrane microdomains, endolysosomal and cytosolic lipid storage leading to phospholipidosis, and lipid droplet accumulation or activation of lipid efflux either through the Golgi system or bypassing this organelle on the way to the plasma membrane. The interdependence of these pathways and pharmacological modifications are described. The monocyte innate immunity receptor complex in defining monocyte subpopulations and their role in cardiovascular disease is taken into account. The composition of certain molecular lipid species in membrane microdomains and other organelles is essential for cellular functions affecting raft dynamics, signal transduction, and membrane and organelle trafficking. It is very likely that the underlying defects in lipid-associated rare genetic diseases such as ABCA1 deficiency, Niemann–Pick disease type C, as well as the more frequent complex disorders associated with atherosclerosis and phospholipidosis are related to disturbances in membrane homeostasis, signal transduction, and cellular lipid metabolism.

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Abbreviations

ABCA1:

ATP binding cassette transporter A1

ABCG1:

ATP binding cassette transporter G1

ACAT1:

Acyl-coenzyme A:cholesterol acyltransferase 1

AGE:

Advanced glycation end product

Apo:

Apolipoprotein

ARF:

ADP-ribosylation factor (ARF)-like

CAD:

Coronary artery disease

CETP:

Cholesteryl ester transfer protein

CR:

Complement receptor

CRP:

C-reactive protein

CSF-1:

Colony-stimulating factor-1

DRM:

Detergent resistant membrane

E-LDL:

Enzymatically degraded LDL

ER:

Endoplasmatic reticulum

FADD:

Fas-associated death domain

FCDR-assay:

Flow cytometric differential detergent resistance assay

FRET:

Fluorescence resonance energy transfer

FcγR:

Fcγ receptor

GPI:

Glycosylphosphatidylinositol

HDL:

High-density lipoproteins

HMG-CoA:

3-Hydroxy-3-methylglutaryl coenzyme A

ITAM:

Immunoreceptor tyrosine-based activation motifs

ITIM:

Immunoreceptor tyrosine-based inhibition motifs

LDL:

Low-density lipoproteins

LOX-1:

Lectin-like Ox-LDL receptor

LPS:

Lipopolysaccharide

LXR:

Liver X receptor

MARCO:

Macrophage scavenger receptor with collagenous structure

MPO-LDL:

Myeloperoxidase oxidized LDL

mTOR:

Mammalian target of rapamycin

NPC1:

Niemann–Pick disease C1

Ox-LDL:

Oxidized LDL

PPAR:

Peroxisome proliferators-activated receptor

PPRE:

Peroxisome proliferation response element

RAGE:

Receptor for advanced glycation end-products

RXR:

Retinoid X receptor

SCAP:

SREBP-cleavage activation protein

SIRS:

Systemic inflammatory response syndrome

SR-BI:

Scavenger receptor BI

SREBP:

Sterol regulatory element binding protein

SREC:

Scavenger receptor expressed by endothelial cells

SR-PSOX:

Scavenger receptor for phosphatidylserine and oxidized lipoprotein

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Authors and Affiliations

  1. Institute for Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, 93042, Regensburg, Germany

    G. Schmitz & M. Grandl

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  1. G. Schmitz
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Correspondence to G. Schmitz .

Glossary

Advanced glycation end products (AGEs):

AGEs are the result of a chain of chemical reactions after an initial nonenzymatic glycosylation. AGEs can be formed exogenously by heating sugars with fats or proteins, or endogenously through normal metabolism and aging. AGEs are thought to be major factors in aging and age-related chronic diseases.

Apolipoprotein A-I (ApoA-I):

ApoA-I is the major protein component of HDL in plasma. The protein helps to clear cholesterol from arteries and promotes cholesterol efflux form tissues to the liver for excretion. It is a cofactor for lecithin cholesterol acyltransferase (LCAT), which is responsible for the formation of most plasma cholesteryl esters.

ATP-binding cassette transporter ABCA1 (member 1 of human transporter subfamily ABCA):

ABCA1 is a human protein and gene. This transporter is a major regulator of cellular cholesterol and phospholipids homeostasis. ABCA1 functions as a cholesterol efflux pump in the cellular lipid removal pathway.

Autophagy:

Autophagy, or autophagocytosis, is a catabolic process involving the degradation of a cell's own components through the lysosomal machinery. It is a tightly regulated process that plays a normal part in cell growth, development, and homeostasis, helping to maintain a balance between the synthesis, degradation, and subsequent recycling of cellular products. It is a major mechanism by which a starving cell reallocates nutrients from unnecessary processes to more essential processes.

Complement receptor 3 (CD11b/CD18):

Integrin alpha M (ITGAM, CR3A or CD11b) and integrin β2 (ITGB2 or CD18) form the heterodimeric integrin alpha-M beta-2 (αMβ2) molecule, also known as macrophage-1 antigen (Mac-1) or complement receptor 3 (CR3). Integrins are integral cell-surface proteins composed of an alpha chain and a beta chain. Integrins are known to participate in cell adhesion and migration as well as cell-surface-mediated signaling. αMβ2 is expressed on the surface of many leukocytes involved in the innate immune system. Furthermore, it plays a role in the complement system due to its capacity to bind inactivated complement component 3b (iC3b).

Glycerophospholipids:

Glycerophospholipids or phosphoglycerides are glycerol-based phospholipids. They are the main component of biological membranes.

Glycosphingolipids (GSLs):

GSLs are ceramide derivatives containing more than one sugar residue and are constituents of lipid membrane microdomains.

Lipopolysaccharide (LPS):

LPS is a large molecule consisting of a lipid and a polysaccharide (carbohydrate). LPS acts as the prototypical endotoxin, because it binds the CD14/TLR4/MD2 receptor complex, which promotes the secretion of proinflammatory cytokines in many cell types, but especially in macrophages.

Niemann–Pick disease:

Niemann–Pick disease is an autosomal recessive disorder affecting lipid metabolism resulting in an accumulation of harmful amounts of lipids in the spleen, liver, lungs, bone marrow, and brain. There are three variants (A, B, and C) of Niemann–Pick disease based on the genetic cause and the symptoms exhibited by the patient.

Phagocytosis:

Phagocytosis is the cellular process of engulfing solid particles by the cell membrane to form an internal phagosome (vacuole formed around a particle). The phagosome is usually delivered to the lysosome where it fuses with the lysosome and forms a phagolysosome.

Phospholipidosis:

Phospholipidosis is a lipid storage disorder which is characterized by lamellar body formation and excess phospholipid accumulation within cells. Drug-induced phospholipidosis is an adverse drug reaction that occurs with many cationic amphiphilic drugs.

Receptor for advanced glycation end products (RAGE):

RAGE is expressed by many cells in the body (e.g., endothelial cells, smooth muscle cells, or cells of the immune system). When binding AGEs, RAGE contributes to age- and diabetes-related chronic inflammatory diseases such as atherosclerosis, asthma, arthritis, and myocardial infarction.

Tangier disease:

Tangier disease is a rare autosomal recessive disorder characterized by a severe reduction in the amount of HDL in the bloodstream, which is a risk factor for CAD. People with Tangier disease have defective ABCA1 transporters resulting in a greatly reduced ability to transport cholesterol out of their cells, leading to an accumulation of cholesterol in many body tissues.

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Schmitz, G., Grandl, M. (2008). Lipid homeostasis in macrophages – Implications for atherosclerosis. In: Reviews of Physiology Biochemistry and Pharmacology. Reviews of Physiology, Biochemistry and Pharmacology, vol 160. Springer, Berlin, Heidelberg. https://doi.org/10.1007/112_2008_802

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