negative regulation of receptor-mediated endocytosis involved in cholesterol transport

Definition

Target type: biologicalprocess

Any process that stops, prevents or reduces the frequency, rate or extent of receptor-mediated endocytosis involved in cholesterol transport. [GO_REF:0000058, GOC:BHF, GOC:nc, GOC:TermGenie, PMID:22848640]

Negative regulation of receptor-mediated endocytosis involved in cholesterol transport is a complex process that fine-tunes the uptake of cholesterol from the bloodstream. Here's a detailed breakdown:

1. **LDL Receptor Binding and Internalization:**
- Low-density lipoprotein (LDL), the primary carrier of cholesterol in the blood, binds to LDL receptors (LDLR) on the cell surface.
- This binding initiates the process of endocytosis, where the LDLR-LDL complex is internalized into the cell within clathrin-coated pits.
2. **Clathrin-Mediated Endocytosis:**
- The plasma membrane invaginates, forming clathrin-coated pits, which are small depressions containing LDLR-LDL complexes.
- Clathrin, a protein coat, helps shape these pits and ultimately pinch off the vesicles containing the LDLR-LDL complex.
3. **Vesicle Trafficking:**
- The clathrin-coated vesicles lose their coat and fuse with early endosomes, acidic compartments within the cell.
4. **LDL Dissociation:**
- The acidic environment within the early endosome causes the LDLR-LDL complex to dissociate.
5. **Recycling of LDL Receptors:**
- LDLRs are recycled back to the cell surface via transport vesicles, ensuring continued uptake of LDL.
- This recycling process is essential for maintaining the cell's cholesterol balance.
6. **Lysosomal Degradation of LDL:**
- LDL particles remain within the early endosome and are transported to late endosomes and ultimately lysosomes.
- Lysosomes contain hydrolytic enzymes that break down the LDL, releasing cholesterol for cellular use.

**Negative Regulation Mechanisms:**

- **Regulation of LDL Receptor Expression:** The number of LDLRs on the cell surface is tightly regulated.
- High cholesterol levels within the cell trigger a reduction in LDLR synthesis, decreasing LDL uptake.
- Conversely, low cholesterol levels lead to increased LDLR expression, enhancing LDL uptake.
- **Internalization and Degradation of LDLR:**
- Some LDLRs undergo internalization and degradation in the lysosomes, reducing their availability for LDL uptake.
- **Adaptor Protein Complex 2 (AP2):**
- AP2 plays a critical role in the formation of clathrin-coated pits and the recruitment of LDLRs to these sites.
- Regulatory mechanisms can interfere with AP2 function, impacting LDLR internalization.
- **Protein Kinase A (PKA) Signaling:**
- PKA phosphorylation can regulate LDLR trafficking and recycling, impacting LDL uptake.
- **Sterol Regulatory Element-Binding Protein (SREBP) Pathway:**
- SREBPs are transcription factors that control the expression of genes involved in cholesterol biosynthesis and LDLR expression.
- Negative regulation can occur at the level of SREBP activation, influencing cholesterol synthesis and LDLR levels.

**In summary, negative regulation of receptor-mediated endocytosis involved in cholesterol transport is a multi-layered process that ensures appropriate levels of cholesterol within cells. This regulation involves controlling LDLR expression, trafficking, and recycling, along with intricate signaling pathways that respond to cellular cholesterol status.'
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