Lipids have been considered key mediators that can regulate cellular processes, and may induce multiple signaling pathways. In addition, the use of lipid metabolites as cell biomarkers can indicate different biological states and cell activities. The total content of lipids in the cell is the lipidome. Any modification in the cellular lipidome induces or regulates signaling associated with cell function.

Lipid metabolites including very low-, intermediate-, and low-density lipoprotein (VLDL, IDL, and LDL) particles, have been reported to be positively associated with cardiovascular diseases such as MI and ischemic stroke (IS). In contrast, high-density lipoprotein (HDL) particles have been shown to be inversely correlated with MI occurrence. The process of adipocyte formation, also known as adipogenesis, is regulated by a network of complex molecular processes, and this regulatory mechanism may also be affected by lipoproteins. Thus, we assume that lipoproteins regulate differentiation into cardiomyocyte and endothelial cells, thereby affecting heart tissue function and regeneration. Lipoproteins include cholesterol, triglycerides, and phospholipids. These blood lipids are fat-soluble, and must be combined with plasma proteins to form lipoproteins before they can be transported to various organs and tissues by the blood.

 High-density lipoprotein (HDL)

A total of 20–30% of the plasma in the blood is transported by high-density lipoproteins, mainly to bring the plasma of the surrounding tissues back for insulin metabolism. The higher a person’s level of HDL, the lower their chance of having coronary heart disease, so HDL-cholesterol is called “good” plasma. The main content of HDL is phospholipids, including phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphatidylinositol (PI). Sphingolipids and cholesterol primarily serve as building blocks for membranes and organelles. Polyunsaturated fatty acid (PUFA)-containing lipid species increase in the mature stages of mesenchymal stromal cells derived from human fetal membranes (hFM-MSCs). Chatgilialoglu et al. found that culturing hFM-MSCs in vitro changes their fatty acid composition. In order to maintain and improve the functional properties of hFM-MSCs, tailored lipid supplements can mimic membrane environments similar to its physiological counterparts. Stem cells can also be used in patients to achieve therapeutic outcomes. The results also suggest that there is an association between phospholipids and mesenchymal stromal cell differentiation. 

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 Low-density lipoprotein (LDL)

Sixty to seventy percent of cholesterol in the blood is carried by low-density lipoproteins, mainly to bring cholesterol from the liver to the surrounding tissues. Hypercholesterolemia caused by excessive low-density lipoprotein cholesterol is a risk factor for coronary atherosclerosis and heart disease, so low-density lipoprotein cholesterol is called “bad” cholesterol. Increasing evidence is emerging to support that idea that lipids/lipoproteins cause lipotoxicity toward cardiac tissue, including cardiac muscle, valves, and blood vessels. Low-density lipoproteins (LDLs) have been reported to have a cytotoxic role in inducing atherosclerotic disease, as well as playing a role in chronic inflammatory disorder. The most typical oxidized LDL (oxLDL) is known to have a considerable relationship with coronary artery disease (CAD). LDLs with negative charges can be separated into five subclasses, from L1 to L5, all exhibiting the ability of vascular cells to promote atherogenesis. Among them, L5, which carries the strongest negative charge among the LDLs of patient plasma, was found to be associated with an increased risk of cardiovascular disease, comparable to the risk of smoking, hypercholesterolemia, type 2 diabetes mellitus, and metabolic syndrome. L5 contains higher total protein and triglycerides, but relatively few cholesterol esters, compared with L1, suggesting that the lipotoxicity of L5 activates the related various adhesion molecules and chemokines through cellular processes. Lectin-like oxidized LDL receptor-1 (LOX-1) has been shown to have a high binding affinity for negatively charged ligands, which facilitates downstream signaling transduction of, for example, the Bcl-2 family, leading to cell death. The association of LDL and L5-LDL with the risk of coronary artery disease (CAD) is still being investigated, along with the mechanisms of how those lipoproteins affect related tissues and cells螢幕快照 2021 10 24 下午10.52.01

Very low-density lipoprotein (VLDL)

We have also reported that very low-density lipoprotein (VLDL) can be separated into five different types, defined by the negative charge and known as V1 to V5, with different biological functions. We found that V5 exhibited the greatest degree of cytotoxicity of all the VLDLs in the patient’s plasma, and that patients with metabolic syndrome had a higher percentage of VLDLs in the plasma than normal people. Metabolic syndrome (MetS) patients had significantly higher percentages and higher concentrations of V5/VLDL than the normal population. An abnormally high content of V5-rich VLDL may increase the risk of diabetes, and related vascular lesions and cardiomyopathy. Dyslipidemia is easily link to atrial fibrillation (AF), which can be the originated from several cardiovascular diseases, including heart failure, hypertension, myocardial infarction, valvular heart disease, and rheumatic heart disease. We have shown that the VLDLs in MetS patients (msVLDL) can cause significant left atrial dilation compared with normal VLDLs in treated mice, along with a decreased ejection fraction, and accompanied by unprovoked AF in elderly msVLDL mice. Our evidence indicates the pivotal cytotoxic role of VLDL in cardiomyocyte and AF pathogenesis. These data indicate the potential toxic nature of VLDLs and LDLs toward human tissues, especially cardiac tissue, which can be associated with the occurrence of cardiac disease.