SREBP signaling pathway

Definition

Target type: biologicalprocess

The series of molecular signals from the endoplasmic reticulum to the nucleus generated as a consequence of decreased levels of one or more sterols (and in some yeast, changes in oxygen levels) and which proceeds through activation of a sterol response element binding transcription factor (SREBP) to result in up-regulation of target gene transcription. [GOC:bf, GOC:mah, GOC:signaling, GOC:vw, PMID:12923525, PMID:22017871]

The SREBP (Sterol Regulatory Element Binding Protein) signaling pathway is a complex cellular mechanism that regulates the synthesis of cholesterol, fatty acids, and other lipids. It plays a crucial role in maintaining lipid homeostasis within cells and the body. Here's a detailed breakdown of the process:

**1. SREBP Precursor Synthesis and Processing:**

* SREBPs are synthesized as inactive precursor proteins bound to the endoplasmic reticulum (ER) membrane. There are two main isoforms: SREBP-1a, SREBP-1c, and SREBP-2, each with distinct functions.
* SREBP-1a and -1c primarily regulate fatty acid biosynthesis, while SREBP-2 primarily controls cholesterol biosynthesis.

**2. Sensing Cholesterol Levels:**

* The ER membrane contains SREBP cleavage-activating protein (SCAP), which acts as a cholesterol sensor. When cholesterol levels are low, SCAP escorts the SREBP precursor to the Golgi apparatus.
* Within the Golgi, SREBP encounters two proteases: S1P and S2P.

**3. SREBP Proteolytic Activation:**

* S1P cleaves the SREBP precursor at the N-terminus.
* Subsequently, S2P cleaves the C-terminus, releasing the mature SREBP transcription factor.

**4. Nuclear Translocation and Gene Regulation:**

* The mature SREBP translocates to the nucleus, where it acts as a transcription factor.
* SREBP binds to specific DNA sequences called sterol regulatory elements (SREs) located in the promoter regions of genes involved in lipid synthesis.
* Binding to SREs activates the transcription of target genes, leading to increased production of enzymes involved in cholesterol and fatty acid biosynthesis.

**5. Feedback Regulation:**

* The SREBP pathway is tightly regulated by feedback mechanisms.
* Increased cholesterol levels activate the enzyme Insig, which inhibits SREBP processing and nuclear translocation, effectively downregulating the pathway.
* This ensures that cholesterol synthesis is kept in check to maintain proper levels within cells.

**6. Key Enzymes Regulated by SREBPs:**

* **Cholesterol biosynthesis:** HMG-CoA reductase, squalene synthase, lanosterol synthase
* **Fatty acid biosynthesis:** Acetyl-CoA carboxylase, fatty acid synthase

**7. Importance of SREBP Signaling:**

* The SREBP pathway is essential for normal growth and development, ensuring adequate production of lipids for cell membranes, hormones, and other vital functions.
* Dysregulation of SREBP signaling has been implicated in various diseases, including cardiovascular disease, hypercholesterolemia, and cancer.

**8. Therapeutic Targets:**

* The SREBP pathway is a promising therapeutic target for treating diseases associated with lipid metabolism disorders.
* Drugs that inhibit SREBP activity or its downstream targets have shown potential for lowering cholesterol levels and reducing cardiovascular risk.

**In summary, the SREBP signaling pathway is a crucial cellular mechanism for maintaining lipid homeostasis. It responds to changes in cholesterol levels, orchestrating the synthesis of essential lipids. Dysregulation of this pathway can lead to various health problems, highlighting its significance in human health and disease.**'"

Proteins (2)

Compounds (3)