positive regulation of low-density lipoprotein particle clearance

Definition

Target type: biologicalprocess

Any process that activates or increases the frequency, rate or extent of low-density lipoprotein particle clearance. [GO_REF:0000058, GOC:BHF, GOC:nc, GOC:TermGenie, PMID:22848640]

Positive regulation of low-density lipoprotein (LDL) particle clearance is a complex biological process that involves multiple steps and several key players. It is essential for maintaining cholesterol homeostasis and preventing the accumulation of LDL in the blood, which can lead to atherosclerosis and cardiovascular disease.

**1. LDL Receptor Binding and Internalization:**
The process begins with the binding of LDL particles to LDL receptors (LDLRs) on the surface of cells, primarily hepatocytes. These receptors are transmembrane proteins with a specific binding site for LDL. Once bound, the receptor-LDL complex undergoes endocytosis, a process where the plasma membrane invaginates and forms a vesicle enclosing the complex.

**2. Lysosomal Degradation:**
The vesicle containing LDL and the LDLR is transported to lysosomes, acidic organelles that contain hydrolytic enzymes. The low pH within the lysosome causes the LDL particle to dissociate from the LDLR, and the LDL is then broken down into its constituent parts: cholesterol, fatty acids, and apolipoproteins. The LDLR is recycled back to the cell surface.

**3. Regulation of LDLR Expression:**
The expression of LDLRs is tightly regulated to maintain appropriate LDL clearance levels. Several factors influence LDLR expression, including:
* **Cholesterol Levels:** When intracellular cholesterol levels are low, the synthesis of LDLRs is increased, leading to increased LDL uptake. Conversely, when cholesterol levels are high, LDLR synthesis is suppressed.
* **SREBP-2 (Sterol Regulatory Element Binding Protein 2):** This transcription factor plays a crucial role in regulating LDLR gene expression. When cholesterol levels are low, SREBP-2 is activated, leading to increased LDLR transcription and translation.
* **PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9):** This protein promotes the degradation of LDLRs in the liver, reducing LDL clearance.

**4. Other Factors:**
In addition to the mechanisms described above, other factors contribute to LDL clearance, including:
* **Scavenger Receptors:** These receptors can bind and internalize modified LDL particles, such as oxidized LDL, that are not efficiently recognized by LDLRs.
* **Apolipoprotein E (ApoE):** ApoE is a lipoprotein that can bind to LDLRs and facilitate LDL uptake.
* **Lipoprotein Lipase (LPL):** This enzyme hydrolyzes triglycerides in lipoproteins, including LDL, which can enhance LDL clearance.

**5. Disruptions in LDL Clearance:**
Mutations in genes involved in LDL clearance, such as LDLR, PCSK9, and ApoE, can lead to increased LDL levels and increased risk of cardiovascular disease. Additionally, factors like high cholesterol diets, lack of physical activity, and smoking can contribute to impaired LDL clearance.'
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Proteins (1)

Compounds (1)