Liang-Yin Ke (from the Department of Medical Laboratory Science and Biotechnology), Jeng-Hsien Yen (from Graduate Institute of Medicine), the first author Hua-Chen Chan (Center for Lipid Biosciences) and colleagues published the above-named paper in the Arthritis & Rheumatology this year. Immediately, the paper got great attention. The editor of Nature Reviews, Joanna Clarke, interviewed with the corresponding authors, and later she wrote a “research highlight” editorial and published in Nature Reviews Rheumatology, entitled as “LDL subfraction linked to vascular aging and heart disease in SLE.”

Figure 1. An research highlight published in Nat Rev Rheumatol. 2020 Apr;16(4):187.

L5 LDL linked to vascular aging in patients with Systemic Lupus Erythematosus (SLE)

SLE patients often have atherosclerotic complications at a young age but normal low-density lipoprotein (LDL) levels. Thus, this study was aimed to explain the paradoxical findings of early vascular aging (EVA) and normolipidemia in patients with SLE. In KMU, we focused on a different approach: the electronegative LDL. Human plasma LDL can be separated into five subfractions. L5 LDL, in particular, has been shown to be atherogenic, independent of LDL cholesterol. From here, we investigated the mechanisms of vascular aging in SLE patients.

Figure 2. SLE patients show elevated levels of atherogenic lipoproteins, L5 LDL.

The mass spectrometric analysis revealed that lysophosphatidylcholine (LPC) and platelet-activating factor (PAF) were increased in SLE-LDL and L5.

LPC and PAF are bioactive lipids, showing the capability to induce inflammatory changes in vascular cells both in vivo and in vitro. In this study, repeated injections of SLE-LDL, LPC or PAF to apoE^-/- mice led to increases in IMT, collagen deposition, fatty-streak areas in the aortic wall, and cell senescence in the aortic endothelium.

Figure 3. LPC and PAF were increased in SLE-LDL and L5.

SLE-L5 induces CD16+ expression in monocytes and monocyte adhesion to ECs through CX3CL1-CX3CR1 interactions.

Flow cytometric analysis showed that SLE-L5 lipids, but not SLE-L1 lipids, induced an increase in the percentage of CD16+ monocytes, which are CX3CR1 expressing cells. On the other hand, SLE-LDL induces CX3CL1 expression in activated endothelial cells. Through CX3CL1-CX3CR1 interactions, SLE-L5 induces early atherosclerotic changes in young apoE^-/- mice. SLE-L5 induced significant atherosclerotic lesion formation in the aortic arch of the mice as well as collagen deposition and elastic fragmentation in aortas.

Figure 4. : SLE-L5 induced collagen deposition and elastic fragmentation in aortas of mice.

Conclusion. L5 LDL (the most electronegative subfraction) is increased in SLE patients. By mass spectrometry, results showed that L5 LDL is an LPC- and PAF-rich lipoprotein. Through CX3CL1-CX3CR1 interactions between ECs and CD16+ monocytes, L5 LDL promotes atherosclerosis. Our findings suggest that the L5 level, not the total LDL concentration, should be a therapeutic target for preventing EVA and atherosclerosis in patients with SLE.

Graphical abstract