low-density lipoprotein particle mediated signaling

Definition

Target type: biologicalprocess

The series of molecular signals mediated by the detection of low-density lipoprotein particle. [GOC:BHF, GOC:rl, PMID:16013438]

Low-density lipoprotein (LDL) particles, the primary carriers of cholesterol in the blood, play a crucial role in signaling pathways that regulate various cellular processes. The intricate signaling cascade initiated by LDL particles involves receptor-mediated endocytosis, intracellular trafficking, and subsequent activation of downstream signaling molecules. Here is a detailed explanation of the biological process of LDL particle-mediated signaling:

1. **Receptor-mediated endocytosis**: The process begins with LDL particles binding to the LDL receptor (LDLR) on the cell surface. LDLRs are transmembrane proteins that specifically recognize and bind to apolipoprotein B-100 (apoB-100), the protein component of LDL particles. Upon binding, the LDLR-LDL complex is internalized by the cell through clathrin-mediated endocytosis. This involves the formation of clathrin-coated pits, which invaginate and pinch off from the plasma membrane to form vesicles containing the LDL-LDLR complex.

2. **Intracellular trafficking**: The LDL-containing vesicles are transported to early endosomes, acidic compartments where the LDLR-LDL complex dissociates due to the low pH. The released LDL particles are then delivered to lysosomes, the cellular degradative organelles, where the cholesterol esters within the LDL are hydrolyzed by lysosomal enzymes. Free cholesterol is then released and can be used for various cellular functions, including membrane synthesis and steroid hormone production.

3. **Signal transduction**: In addition to cholesterol delivery, LDL particles can also trigger signal transduction pathways. Upon binding to LDLRs, LDL particles can activate several signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway, the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, and the protein kinase C (PKC) pathway. These pathways contribute to various cellular responses, including cell proliferation, survival, and inflammation.

4. **Regulation of cholesterol homeostasis**: One of the primary functions of LDL-mediated signaling is to regulate cholesterol homeostasis. LDL particles serve as a source of cholesterol for cells. When cellular cholesterol levels are low, the expression of LDLRs is increased, leading to increased uptake of LDL particles. Conversely, when cellular cholesterol levels are high, the expression of LDLRs is decreased, reducing LDL uptake. This feedback loop helps to maintain cholesterol levels within a narrow range.

5. **Inflammation and atherosclerosis**: LDL particles, particularly when oxidized, can contribute to inflammation and atherosclerosis, a disease characterized by the buildup of plaque in arteries. Oxidized LDL can trigger the release of inflammatory mediators from macrophages, leading to the formation of foam cells, a hallmark of atherosclerotic plaques. These foam cells contribute to plaque growth and can eventually lead to artery blockage and heart attack.

6. **Metabolic disorders**: Dysregulation of LDL-mediated signaling can contribute to metabolic disorders, including hypercholesterolemia, a condition characterized by high levels of LDL cholesterol in the blood. Increased levels of LDL cholesterol can lead to atherosclerosis and other cardiovascular diseases.

In conclusion, LDL particles are not only carriers of cholesterol but also active signaling molecules that regulate various cellular processes. Their ability to modulate cholesterol homeostasis, activate signaling pathways, and contribute to inflammatory responses highlights their crucial role in maintaining cellular health and preventing disease.'
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