Dyslipidemia in rheumatoid arthritis: the possible mechanisms

Abstract

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease, of which the leading cause of death is cardiovascular disease (CVD). The levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), and high-density lipoprotein cholesterol (HDL-c) in RA decrease especially under hyperinflammatory conditions. It is conflictive with the increased risk of CVD in RA, which is called "lipid paradox". The systemic inflammation may explain this apparent contradiction. The increased systemic proinflammatory cytokines in RA mainly include interleukin-6(IL-6)、interleukin-1(IL-1)and tumor necrosis factor alpha(TNF-α). The inflammation of RA cause changes in the subcomponents and structure of HDL particles, leading to a weakened anti-atherosclerosis function and promoting LDL oxidation and plaque formation. Dysfunctional HDL can further worsen the abnormalities of LDL metabolism, increasing the risk of cardiovascular disease. However, the specific mechanisms underlying lipid changes in RA and increased CVD risk remain unclear. Therefore, this article comprehensively integrates the latest existing literature to describe the unique lipid profile of RA, explore the mechanisms of lipid changes, and investigate the impact of lipid changes on cardiovascular disease.

Keywords: cardiovascular disease; dyslipidemia; high-density lipoprotein cholesterol; low-density lipoprotein cholesterol; mechanism; rheumatoid arthritis.

Figure 1

Schematic diagram of the structure of main lipid particles. Lipoproteins are complex particles with a hydrophobic core of non-polar lipids, mainly cholesterol esters and total glyceride (TGs). The hydrophobic core is surrounded by a hydrophilic membrane composed of phospholipids, free cholesterol, and apolipoprotein. According to the particle size, lipid composition, and apolipoprotein, lipoproteins are divided into chylomicrons (CM), chylomicron remnants, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and lipoprotein(a) [L p(a)]. CM and VLDL are rich in triglycerides, and LDL is rich in cholesterol.

Figure 2

The schematic diagram of endogenous and exogenous cholesterol pathways. In the exogenous regulation pathway, lipids (cholesterol and triglycerides) from food sources are transferred to CMs through being absorbed into the blood in the small intestine. CMs reach peripheral tissues with the blood and exchange lipoproteins with HDL to obtain apolipoprotein E (Apo E). And CMs is metabolized by lipoprotein lipase (LPL) in fat and muscle cells to generate free fatty acids (FFAs) and chylomicron remnants. FFAs are absorbed by adjacent muscle and fat cells for energy production or storage. As the size of chylomicron decreases, the phospholipids and carrier proteins (Apo A and C) on the surface of the chylomicron are transferred to other lipoproteins (primarily HDL). Apo E on chylomicron remnants binds to LDL receptor (LDLR) and other liver receptors (such as low-density lipoprotein receptor-related protein 1 and syndecan-4), and is absorbed and cleared by liver cells. In the endogenous lipoprotein pathway, VLDL is produced by the liver, and enters the blood. TGs in VLDL is metabolized by LPL in peripheral tissues and generate FFAs and IDL. Those IDL particles are relatively enriched in cholesterol esters and obtain Apo E from HDL particles. In a pathway similar to the removal of chylomicron remnants, a small portion (about 50%) of the IDL particles can be removed from circulation by the liver through binding with Apo E and liver receptors, such as LDL and LRP receptors. The remaining TGs in IDL continue to release FFAs by LPL action, and the exchangeable carrier proteins are transferred from IDL particles to other lipoproteins, generating low-density lipoprotein (LDL). About 70% of circulating LDL is cleared by liver cell LDLR-mediated endocytosis, and the rest is absorbed by extra-liver tissues. In the state of RA inflammation, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) produced locally in the joints can enter the circulation. TNF-α and IL-6 can promote LDL metabolism by increasing the expression of LDLR on the surface of liver cells.

Figure 3

Schematic diagram of cholesterol reverse transportation. Reverse cholesterol transport (RCT) is a process that starts with the formation of pro-Apo A-I in the liver and intestines. Bone Morphogenetic Protein-l (BMP-1) converts it into mature Apo A-I. Free cholesterol (FC) from peripheral cells (including macrophages) flows out to the lipid-free Apo A-I by interacting with ATP Binding Cassette Subfamily A Member l (ABCA1), forming disc-shaped nascent HDL particles. The above process is called cholesterol efflux. Apo A-I on the disc-shaped HDL particle directly interacts with Lecithin Cholesterol Acyltransferase (LCAT) synthesized by the liver to convert the disc-shaped HDL into spheroidal HDL particles. Then, LCAT converts cholesterol into Cholesterol Ester (CE), resulting in cholesterol esterification and HDL maturation. Mature HDL can also obtain additional cholesterol from cells through enzyme ATP-binding cassette transporter G1 (ABCG1) and scavenger receptor B1 (SR-B1). In the direct pathway, the HDL particle docks with SR-B1, which regulates the transfer of cholesterol from HDL particles to cells. In the indirect pathway, the cholesterol transferred by HDL particles is transferred to lipoproteins containing Apo B (e.g., LDL-c and VLDL-c) through cholesterol ester transfer protein (CETP). At the same time, phospholipid transfer protein (PLTP) transfers phospholipid (PL) from lipoproteins containing Apo B to HDL. Finally, both the direct and indirect RCT pathways result in the transfer of cholesterol from peripheral sites (mostly macrophages) to the liver and excretion through bile. In the state of RA inflammation, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β) produced locally in the joints can enter the circulation. TNF-α and IL-6 can promote LDL metabolism by increasing the expression of LDLR and SR-B1 on the surface of liver cells. TNF-α and IL-1β can inhibit the production of pro-Apo A-I particles in the liver, suppressing HDL generation. As a result, levels of both HDL and LDL in RA decrease.

Figure 4

The altered protein components of pro-inflammatory HDL in patients with Rheumatoid Arthritis (RA). Rheumatoid arthritis (RA) patients have lower levels of anti-inflammatory and antioxidant proteins that are associated with HDL’s anti-inflammatory functionality. These proteins include Apolipoprotein A-I (Apo A-I), Paraoxonase-1 (PON-1), Platelet-activating Factor Acetyl Hydrolase (PAF-AH), LCAT, CETP, and Apo J etc. However, the levels of pro-inflammatory proteins such as Serum amyloid A (SAA), Ceruloplasmin (Cp), Transferrin (Tf), and myeloperoxidase (MPO) are increased.

Figure 5

The core role of ox-LDL in the pathogenesis of atherosclerosis in patients with rheumatoid arthritis (RA). Under pathological conditions such as hypertension, hypercholesterolemia, smoking, and hyperglycemia, the vascular endothelium becomes damaged. Lipoprotein containing Apo B in plasma penetrates damaged endothelial cells into tunica intima. At the same time, the damaged endothelium expresses monocyte adhesion molecules, allowing monocytes to enter the intima and produce reactive oxygen species (ROS) to oxidize LDL to be oxidized-LDL (Ox-LDL). Ox-LDL attracts more monocytes to the site, which differentiate into macrophages. Macrophages constantly internalize ox-LDL through scavenger receptors CD36, lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1), scavenger receptor class A type I/II (SR-AI/II) and class B type I(SR-BI), to accumulate as foam cells. Foam cells die, releasing their contents outside and being engulfed again by other macrophages. Ultimately, a large lesion area forms and gradually progresses into an atherosclerotic plaque. The atherosclerotic characteristics of ox-LDL can be summarized as: increasing the synthesis and secretion of adhesion molecules, chemotaxis and adhesion of monocytes, cytotoxicity to endothelial cells, enhancing foam cell formation, and increasing proliferation of smooth muscle cells. In addition, the lack of recognition of ox-LDL structure by LDLR prevents normal metabolism of LDL particles, leading to the development of atherosclerosis. In particular, under inflammatory conditions of RA, TNF, IL-6, and interferon-α (IFN-α) can enhance SR-A, LOX-1 or CD36 expression on the surface of macrophages by increasing its promoter activity in peripheral blood monocytes, thereby increasing ox-LDL uptake and enhancing foam cell formation. Elevated sdLDL in RA can promote foam cell formation and the development of atherosclerosis by regulating lipid metabolism, inducing inflammation, and enhancing endothelial injury, making itself more easily oxidized and penetrating the endothelium. Elevated Myeloperoxidase (MPO) in RA can promote LDL oxidation, leading to the formation of Mox-LDL. The clearance of Mox-LDL is reduced, exacerbating the formation of foam cells and atherosclerosis.