Cholesterol synthesis is inhibited when intracellular cholesterol levels are high. Which transcription factor is responsible for sensing cellular cholesterol status and downregulating HMG-CoA reductase gene expression?

Explanation

## SREBP: The Cholesterol Sensor **Key Point:** SREBP (Sterol Regulatory Element-Binding Protein) is a membrane-bound transcription factor that directly senses intracellular cholesterol levels and regulates the expression of genes involved in cholesterol and lipid synthesis. **High-Yield:** SREBP exists in an inactive form bound to the ER membrane when cholesterol is abundant. When cholesterol is depleted, SREBP is released, travels to the nucleus, and activates transcription of HMG-CoA reductase and other lipogenic genes. ## SREBP Regulation Pathway ```mermaid flowchart TD A[High intracellular cholesterol]:::outcome --> B[SREBP remains bound to ER/Golgi membrane]:::action B --> C[Transcription of HMG-CoA reductase BLOCKED]:::action C --> D[Cholesterol synthesis DECREASES]:::outcome E[Low intracellular cholesterol]:::outcome --> F[SREBP cleaved and released from membrane]:::action F --> G[SREBP enters nucleus]:::action G --> H[Binds SRE sequences on HMG-CoA reductase promoter]:::action H --> I[Transcription of HMG-CoA reductase ACTIVATED]:::action I --> J[Cholesterol synthesis INCREASES]:::outcome ``` ## Key Regulatory Features | Mechanism | Effect | | --- | --- | | **SREBP cleavage** | Requires low cholesterol; mediated by SCAP (SREBP cleavage-activating protein) and Insig proteins | | **Target genes** | HMG-CoA reductase, HMG-CoA synthase, squalene synthase, LDL receptor | | **Feedback inhibition** | High cholesterol → SREBP inactive → reduced enzyme synthesis | | **Transcriptional regulation** | SREBP binds SRE (sterol regulatory elements) in promoter regions | **Clinical Pearl:** Statins lower intracellular cholesterol, which paradoxically activates SREBP and increases HMG-CoA reductase transcription. This is why statin doses must be escalated over time and why combination therapy (e.g., statin + ezetimibe) is often needed. **Mnemonic:** **SREBP** = **S**terol **RE**gulatory **E**lement-**B**inding **P**rotein — the master switch for cholesterol homeostasis.