Regarding the regulation of cholesterol synthesis, all of the following statements are TRUE EXCEPT:

Explanation

## Regulation of Cholesterol Synthesis — Key Regulatory Mechanisms **Key Point:** SREBP (Sterol Regulatory Element Binding Protein) is a transcription factor that is **activated when cholesterol is LOW**, not high. This is a critical feedback mechanism. ### SREBP Activation Pathway When intracellular cholesterol is **depleted**: 1. SREBP is released from the endoplasmic reticulum membrane 2. It translocates to the nucleus 3. It binds to sterol regulatory elements (SREs) in the promoter regions of genes encoding: - HMG-CoA reductase (rate-limiting enzyme) - HMG-CoA synthase - LDL receptor - Other cholesterol synthesis enzymes 4. Result: **Increased transcription** of cholesterol synthesis genes When intracellular cholesterol is **abundant**: 1. SREBP remains bound to the ER membrane (via SCAP and Insig proteins) 2. SREBP **cannot** enter the nucleus 3. Transcription of synthesis genes **decreases** ### Why Each Statement Is Correct (Except Option 1) | Statement | Status | Explanation | |-----------|--------|-------------| | HMG-CoA reductase inhibition by cholesterol | ✓ Correct | Cholesterol and its derivatives (oxysterols) allosterically inhibit the enzyme and promote its degradation via ubiquitination | | SREBP activation at LOW cholesterol | ✓ Correct | SREBP is the master regulator — activated when cholesterol is scarce, not abundant | | LDL receptor downregulation at HIGH cholesterol | ✓ Correct | High cholesterol suppresses SREBP, reducing LDL receptor transcription, thereby reducing cellular cholesterol uptake | | AMPK inactivates HMG-CoA reductase | ✓ Correct | During energy stress (high AMP/ATP ratio), AMPK phosphorylates and inactivates the enzyme, conserving ATP | **High-Yield:** The SREBP mechanism is a **double negative feedback loop**: high cholesterol → SREBP stays inactive → less synthesis genes transcribed → cholesterol production decreases. **Warning:** Students often confuse the direction of SREBP regulation. Remember: **SREBP is active when cholesterol is LOW** (it acts as a "cholesterol sensor" that says "we need more"). ### Mnemonic **SREBP = "Sterol Response — Elevated Biosynthesis Protein"** — it responds to **low** sterol by **elevating** biosynthesis.