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Bibliografia__________________________________________________________________________

(1) Knuplez E, Marsche G. An Updated Review of Pro- and Anti-Inflammatory Properties of Plasma Lysophosphatidylcholines in the Vascular System. Int J Mol Sci. 2020 Jun 24;21(12):4501. doi: 10.3390/ijms21124501. 

Abstract. Lysophosphatidylcholines are a group of bioactive lipids heavily investigated in the context of inflammation and atherosclerosis development. While present in plasma during physiological conditions, their concentration can drastically increase in certain inflammatory states. Lysophosphatidylcholines are widely regarded as potent pro-inflammatory and deleterious mediators, but an increasing number of more recent studies show multiple beneficial properties under various pathological conditions. Many of the discrepancies in the published studies are due to the investigation of different species or mixtures of lysophatidylcholines and the use of supra-physiological concentrations in the absence of serum or other carrier proteins. Furthermore, interpretation of the results is complicated by the rapid metabolism of lysophosphatidylcholine (LPC) in cells and tissues to pro-inflammatory lysophosphatidic acid. Interestingly, most of the recent studies, in contrast to older studies, found lower LPC plasma levels associated with unfavorable disease outcomes. Being the most abundant lysophospholipid in plasma, it is of utmost importance to understand its physiological functions and shed light on the discordant literature connected to its research. LPCs should be recognized as important homeostatic mediators involved in all stages of vascular inflammation. In this review, we want to point out potential pro- and anti-inflammatory activities of lysophospholipids in the vascular system and highlight recent discoveries about the effect of lysophosphatidylcholines on immune cells at the endothelial vascular interface. We will also look at their potential clinical application as biomarkers.

Law SH, Chan ML, Marathe GK, Parveen F, Chen CH, Ke LY. An Updated Review of Lysophosphatidylcholine Metabolism in Human Diseases. Int J Mol Sci. 2019 Mar 6;20(5):1149. doi: 10.3390/ijms20051149. 

Abstract. Lysophosphatidylcholine (LPC) is increasingly recognized as a key marker/factor positively associated with cardiovascular and neurodegenerative diseases. However, findings from recent clinical lipidomic studies of LPC have been controversial. A key issue is the complexity of the enzymatic cascade involved in LPC metabolism. Here, we address the coordination of these enzymes and the derangement that may disrupt LPC homeostasis, leading to metabolic disorders. LPC is mainly derived from the turnover of phosphatidylcholine (PC) in the circulation by phospholipase A₂ (PLA₂). In the presence of Acyl-CoA, lysophosphatidylcholine acyltransferase (LPCAT) converts LPC to PC, which rapidly gets recycled by the Lands cycle. However, overexpression or enhanced activity of PLA₂ increases the LPC content in modified low-density lipoprotein (LDL) and oxidized LDL, which play significant roles in the development of atherosclerotic plaques and endothelial dysfunction. The intracellular enzyme LPCAT cannot directly remove LPC from circulation. Hydrolysis of LPC by autotaxin, an enzyme with lysophospholipase D activity, generates lysophosphatidic acid, which is highly associated with cancers. Although enzymes with lysophospholipase A₁ activity could theoretically degrade LPC into harmless metabolites, they have not been found in the circulation. In conclusion, understanding enzyme kinetics and LPC metabolism may help identify novel therapeutic targets in LPC-associated diseases.

Kalia V, Reyes-Dumeyer D, Dubey S, Udhani H, Nandakumar R, Lee AJ, Lantigua R, Medrano M, Rivera D, Honig LS, Mayeux R, Miller GW, Vardarajan BN. Lysophosphatidylcholines are associated with amyloidosis in early stages of Alzheimer's disease. Nat Aging. 2025 Dec 17. doi: 10.1038/s43587-025-01025-7. 

Abstract. Circulating metabolites can identify biochemical risk factors related to Alzheimer's disease (AD). We measured plasma metabolites in 1,068 participants of Caribbean Hispanic ancestry (250 patients with AD and 818 healthy controls) across 2 cohorts and analyzed their relationship with clinical AD, biomarker-supported AD and plasma biomarkers (P-tau181, P-tau217, P-tau231 and Aβ42:Aβ40). Amino acid metabolism pathways were enriched among metabolites associated with P-tau biomarkers, whereas sialic acid and N-glycan pathways were associated with Aβ42:Aβ40. Through several dimensionality reduction approaches, we identified an APOE-ε4 dependent relationship between lysophosphatidylcholines (lysoPCs) carrying polyunsaturated fatty acids and biomarker-supported AD and P-tau biomarkers. In an independent dataset of 110 postmortem brain tissues from non-Hispanic white participants, lysoPCs in the brain were also associated with AD neuropathological features. Our results show that biomarker-based diagnostic criteria identified an APOE-ε4 dependent association with lysoPCs, which play a critical role in the transport of neuroprotective polyunsaturated fatty acids into the brain, and AD. © 2025. The Author(s).

Tseng HC, Lin CC, Wang CY, Yang CC, Hsiao LD, Yang CM. Lysophosphatidylcholine induces cyclooxygenase-2-dependent IL-6 expression in human cardiac fibroblasts. Cell Mol Life Sci. 2018 Dec;75(24):4599-4617. doi: 10.1007/s00018-018-2916-7. 

Abstract. Lysophosphatidylcholine (LysoPC) has been shown to induce the expression of inflammatory proteins, including cyclooxygenase-2 (COX-2) and interleukin-6 (IL-6), associated with cardiac fibrosis. Here, we demonstrated that LysoPC-induced COX-2 and IL-6 expression was inhibited by silencing NADPH oxidase 1, 2, 4, 5; p65; and FoxO1 in human cardiac fibroblasts (HCFs). LysoPC-induced IL-6 expression was attenuated by a COX-2 inhibitor. LysoPC-induced responses were mediated via the NADPH oxidase-derived reactive oxygen species-dependent JNK1/2 phosphorylation pathway, leading to NF-κB and FoxO1 activation. In addition, we demonstrated that both FoxO1 and p65 regulated COX-2 promoter activity stimulated by LysoPC. Overexpression of wild-type FoxO1 and S256D FoxO1 enhanced COX-2 promoter activity and protein expression in HCFs. These results were confirmed by ex vivo studies, where LysoPC-induced COX-2 and IL-6 expression was attenuated by the inhibitors of NADPH oxidase, NF-κB, and FoxO1. Our findings demonstrate that LysoPC-induced COX-2 expression is mediated via NADPH oxidase-derived reactive oxygen species generation linked to the JNK1/2-dependent pathway leading to FoxO1 and NF-κB activation in HCFs. LysoPC-induced COX-2-dependent IL-6 expression provided novel insights into the therapeutic targets of the cardiac fibrotic responses.