GO:0032933 SREBP signaling pathway: Lipid Homeostasis, Genes, Functions and Research Methods
Research-grade guide for scientists and biopharma professionals
Key Takeaways
• GO:0032933 (SREBP signaling pathway) is the endoplasmic reticulum-to-nucleus signaling cascade that activates sterol regulatory element-binding proteins (SREBPs) when sterol levels drop, driving transcription of lipid synthesis genes.
• The pathway is a master regulator of cholesterol, fatty acid, and phospholipid biosynthesis, and its dysregulation is linked to metabolic disease, cancer, and steatosis.
• mTORC1 and Lipin-1 are key upstream regulators that control SREBP nuclear entry in response to nutrient and mechanical cues.
• SREBP signaling intersects with AMPK, AKT, and NF-kB pathways, making it a central node in metabolic and inflammatory signaling.
• CRISPR knockout, point-mutation, knock-in, and overexpression models are essential to dissect causal roles of SREBP pathway components in disease.
• The pathway is a validated therapeutic target; inhibitors such as fatostatin and mitochondria-targeted H2S donors modulate SREBP activity in preclinical models.
Description
The SREBP signaling pathway (GO:0032933) is a fundamental biological process that couples cellular sterol status to transcriptional programs controlling lipid synthesis and uptake. When sterol levels in the endoplasmic reticulum (ER) membrane decrease, sterol regulatory element-binding proteins (SREBPs) are proteolytically activated and translocate to the nucleus, where they up-regulate target genes involved in cholesterol and fatty acid metabolism. This pathway is conserved from yeast to humans and is essential for maintaining membrane lipid homeostasis. Dysregulation of SREBP signaling is a hallmark of many human diseases, including nonalcoholic fatty liver disease, type 2 diabetes, atherosclerosis, and multiple cancers. In hepatocellular carcinoma, SREBP-1 is frequently overexpressed and promotes lipogenesis, making it an attractive therapeutic target. The pathway is also modulated by nutrient-sensing kinases such as mTORC1 and AMPK, which integrate growth factor and energy signals into lipid metabolism. Understanding the molecular mechanisms, regulatory inputs, and disease relevance of SREBP signaling requires robust experimental models. CRISPR-based gene editing enables precise manipulation of pathway components, from complete knockouts to subtle point mutations, facilitating causal inference in metabolic and cancer research.
SREBP signaling pathway At A Glance
| GO ID | GO:0032933 |
|---|---|
| GO term | SREBP signaling pathway |
| Ontology | biological_process |
| Synonym | SREBP-mediated signaling pathway; sterol depletion response; ER-nuclear sterol response pathway |
| Major function | Up-regulation of genes involved in cholesterol, fatty acid, and phospholipid biosynthesis in response to sterol depletion |
| Key regulators | SREBP-1 (SREBF1), SREBP-2 (SREBF2), SCAP, INSIG1/2, mTORC1, Lipin-1 |
| Cellular location | Endoplasmic reticulum membrane, Golgi apparatus, nucleus |
| Disease relevance | Nonalcoholic fatty liver disease, hepatocellular carcinoma, atherosclerosis, type 2 diabetes |
What Is GO:0032933?
GO:0032933, the SREBP signaling pathway, is defined as the series of molecular signals from the endoplasmic reticulum to the nucleus that are generated when sterol levels decrease (and in some yeast, when oxygen levels change). This signaling proceeds through activation of a sterol response element-binding transcription factor (SREBP), leading to up-regulation of target gene transcription. In essence, it is a feedback mechanism that senses sterol depletion and responds by increasing expression of genes required for sterol and lipid biosynthesis.
Why Is SREBP signaling pathway Important in Cell Biology?
The SREBP signaling pathway is critically important because it serves as the master transcriptional regulator of lipid homeostasis, controlling the expression of enzymes and transporters required for cholesterol, fatty acid, and triglyceride synthesis. Its dysregulation contributes to a wide range of metabolic disorders and cancers, where altered lipid metabolism supports rapid cell proliferation and survival. Moreover, the pathway integrates signals from nutrient sensors such as mTORC1 and AMPK, linking cellular energy status to lipid production. Understanding this pathway is therefore essential for developing therapies targeting dyslipidemia, fatty liver disease, and cancer.
• Controls de novo lipogenesis and cholesterol biosynthesis, maintaining membrane integrity and energy storage.
• Dysregulated in nonalcoholic fatty liver disease and hepatocellular carcinoma, promoting lipid accumulation and tumor growth.
• Regulated by mTORC1 via Lipin-1, connecting growth signals to lipid synthesis.
• Modulated by AMPK, providing a link between energy stress and lipid metabolism.
• Influenced by extracellular matrix mechanical cues through Lipin-1 and SREBP.
• Targeted by pharmacological inhibitors such as fatostatin, which induces ferroptosis in glioblastoma.
• Inhibited by mitochondria-targeted hydrogen sulfide donors, reducing fatty liver and obesity in mice.
• Plays a role in diabetic kidney disease, where FTZ alleviates lipid deposition via AMPK/ACC/SREBP signaling.
• Serves as a therapeutic target for metabolic syndrome and cancer.
• Provides a paradigm for studying ER-to-nucleus signaling and feedback control of lipid metabolism.
What Happens During SREBP signaling pathway?
Sterol sensing and SREBP activation
In simple terms: When cholesterol levels drop, a sensor protein called SCAP detects this and escorts SREBP to the Golgi for activation.
In sterol-replete conditions, SREBP is retained in the endoplasmic reticulum (ER) through interaction with INSIG proteins. Upon sterol depletion, SCAP undergoes a conformational change that releases INSIG, allowing the SCAP-SREBP complex to translocate to the Golgi apparatus. There, site-1 protease (S1P) and site-2 protease (S2P) cleave SREBP, releasing its N-terminal transcription factor domain.
Nuclear translocation and target gene activation
In simple terms: The active piece of SREBP moves into the nucleus and turns on genes that make fats and cholesterol.
The cleaved N-terminal fragment of SREBP enters the nucleus and binds to sterol regulatory elements (SREs) in the promoters of target genes, including HMG-CoA reductase, LDL receptor, and fatty acid synthase. This leads to increased transcription of genes involved in cholesterol uptake, biosynthesis, and fatty acid synthesis, restoring lipid homeostasis.
Regulation by mTORC1 and Lipin-1
In simple terms: A nutrient sensor called mTORC1 controls whether SREBP can enter the nucleus by regulating a protein called Lipin-1.
mTORC1 phosphorylates and inhibits Lipin-1, preventing it from dephosphorylating phosphatidic acid and thereby promoting SREBP nuclear entry. When mTORC1 is active, SREBP is able to drive lipogenesis; when mTORC1 is inhibited, Lipin-1 accumulates in the nucleus and suppresses SREBP-dependent transcription.
Integration with AMPK and mechanical cues
In simple terms: Energy stress and physical forces also feed into the SREBP pathway to adjust lipid production.
AMPK activation inhibits SREBP signaling, reducing lipid synthesis under low-energy conditions. Additionally, extracellular matrix stiffness regulates SREBP through Lipin-1, linking mechanical cues to lipid metabolism. These inputs ensure that lipid production matches cellular demands and environmental conditions.
Key Genes Involved in GO:0032933 SREBP signaling pathway
The SREBP signaling pathway involves a core set of genes encoding sterol sensors, proteases, transcription factors, and regulatory kinases.
| Gene | Major Role | Research Relevance |
|---|---|---|
| SREBF1 | Encodes SREBP-1, a transcription factor activating fatty acid and triglyceride synthesis genes | Overexpressed in hepatocellular carcinoma and fatty liver disease; target for metabolic studies |
| SREBF2 | Encodes SREBP-2, primarily regulates cholesterol biosynthesis and uptake genes | Key regulator of cholesterol homeostasis; studied in atherosclerosis and dyslipidemia |
| SCAP | Sterol-sensing escort protein that transports SREBP from ER to Golgi | Essential for SREBP activation; knockout blocks pathway |
| INSIG1 | ER retention protein that binds SCAP and prevents SREBP processing when sterols are abundant | Negative regulator; its expression is feedback-controlled by SREBPs |
| INSIG2 | Homolog of INSIG1 with similar sterol-sensing functions | Modulates SREBP pathway in liver and adipose tissue |
| MBTPS1 | Site-1 protease (S1P) that cleaves SREBP in the Golgi | Required for SREBP activation; mutations affect lipid metabolism |
| MBTPS2 | Site-2 protease (S2P) that performs the second cleavage of SREBP | Essential for releasing the transcription factor domain |
| LPIN1 | Lipin-1, a phosphatidate phosphatase regulated by mTORC1, controls SREBP nuclear entry | Links nutrient signaling to SREBP; knockout alters lipogenesis |
| MTOR | mTOR kinase, part of mTORC1, promotes SREBP activation via Lipin-1 inhibition | Central nutrient sensor; targeted by rapamycin and analogs |
| AKT1 | Serine/threonine kinase that activates mTORC1 and downstream SREBP signaling | Involved in cancer and metabolism; inhibited by fatostatin in glioblastoma |
| PRKAA1 | AMPK catalytic subunit alpha-1; inhibits SREBP and lipogenesis under energy stress | Target for diabetic kidney disease and metabolic syndrome |
| NFKB1 | NF-kB subunit that can be modulated by SREBP pathway cross-talk | Inflammation and lipid metabolism interplay |
| GPX4 | Glutathione peroxidase 4, downstream of AKT/mTORC1; inhibition by fatostatin induces ferroptosis | Links SREBP pathway to ferroptosis in cancer |
| HMGCR | HMG-CoA reductase, rate-limiting enzyme in cholesterol synthesis, a SREBP target gene | Statin target; feedback regulated by SREBP |
| FASN | Fatty acid synthase, SREBP-1 target gene for de novo lipogenesis | Overexpressed in many cancers; metabolic target |
| LDLR | LDL receptor, SREBP-2 target gene for cholesterol uptake | Regulates plasma cholesterol; studied in familial hypercholesterolemia |
| ACC1 | Acetyl-CoA carboxylase 1, SREBP target for fatty acid synthesis | Regulated by AMPK; involved in diabetic kidney disease |
| SCD1 | Stearoyl-CoA desaturase 1, SREBP target for monounsaturated fatty acid synthesis | Modulates membrane fluidity and lipotoxicity |
How Is SREBP signaling pathway Regulated?
The SREBP signaling pathway is tightly regulated at multiple levels. Sterol levels directly control the interaction between SCAP and INSIG proteins, determining SREBP transport to the Golgi. Nutrient and growth factor signaling through mTORC1 modulates SREBP activity by regulating Lipin-1 localization; mTORC1-mediated phosphorylation of Lipin-1 prevents its nuclear entry, thereby permitting SREBP-dependent lipogenesis. Conversely, AMPK activation under energy stress inhibits SREBP and reduces lipid synthesis. Additionally, extracellular matrix stiffness influences SREBP via Lipin-1, integrating mechanical cues into lipid metabolic control. Cross-talk with inflammatory pathways such as NF-kB further modulates SREBP-driven lipogenesis in conditions like fatty liver disease.
SREBP signaling pathway and Human Disease
| Gene | Disease / Biology | Potential Experimental Model |
|---|---|---|
| SREBF1 | Hepatocellular carcinoma, NAFLD | Knockout or overexpression in HepG2 and Huh7 cells; mouse models of NAFLD |
| SREBF2 | Atherosclerosis, hypercholesterolemia | Knockout in HepG2 cells; LDLR-/- mouse models |
| LPIN1 | Lipid metabolism disorders, cancer | Point mutation or knockout in cancer cell lines; mTORC1 regulation studies |
| GPX4 | Ferroptosis in glioblastoma | Knockout or point mutation in glioblastoma cell lines; fatostatin treatment |
| PRKAA1 | Diabetic kidney disease, metabolic syndrome | Knockout or overexpression in renal tubular cells; AMPK activator studies |
SREBP signaling in cancer
In hepatocellular carcinoma, SREBP-1 is frequently overexpressed and drives de novo lipogenesis, supporting rapid tumor growth and survival. Targeting SREBP-1 with pharmacological inhibitors or genetic knockdown reduces tumor proliferation in preclinical models. In glioblastoma, fatostatin, an inhibitor of SREBP activation, induces ferroptosis through inhibition of the AKT/mTORC1/GPX4 signaling axis, highlighting the therapeutic potential of targeting this pathway.
SREBP signaling in metabolic liver disease
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic lipid accumulation, often driven by hyperactive SREBP signaling. Mitochondria-targeted hydrogen sulfide donors reduce fatty liver and obesity in high-fat diet-fed mice by inhibiting de novo lipogenesis and inflammation via mTOR/SREBP-1 and NF-kB pathways. These findings suggest that modulating SREBP activity can ameliorate steatosis and associated metabolic dysfunction.
SREBP signaling in diabetic kidney disease
Diabetic kidney disease (DKD) involves lipid deposition that contributes to renal injury. FTZ, a compound used in traditional medicine, alleviates lipid deposition in DKD by activating the AMPK/ACC/SREBP signaling pathway, thereby reducing lipogenesis. This underscores the role of SREBP in renal lipid metabolism and its potential as a therapeutic target in DKD.
SREBP signaling and mechanotransduction
Extracellular matrix mechanical cues regulate lipid metabolism through Lipin-1 and SREBP, linking tissue stiffness to metabolic reprogramming. This connection is relevant in fibrosis and cancer, where altered matrix stiffness can promote lipogenesis and disease progression.
From SREBP signaling pathway-Related Genes to Experimental Models
| Research Question | Suitable Model |
|---|---|
| Does loss of SREBF1 reduce lipogenesis and tumor growth? | CRISPR knockout of SREBF1 in hepatocellular carcinoma cell lines and xenograft models |
| How do point mutations in SCAP affect sterol sensing? | CRISPR knock-in of specific SCAP mutations in HEK293 or CHO cells |
| What is the role of Lipin-1 phosphorylation in SREBP regulation? | Point mutation of Lipin-1 phosphorylation sites via CRISPR knock-in |
| Can overexpression of SREBP-2 drive cholesterol accumulation? | CRISPR-mediated overexpression of SREBF2 in hepatic cells |
| How does AMPK activation impact SREBP target genes? | Knockout of PRKAA1 or overexpression of constitutively active AMPK in renal cells |
| Does GPX4 mediate fatostatin-induced ferroptosis? | CRISPR knockout of GPX4 in glioblastoma cells followed by fatostatin treatment |
How to Study the SREBP signaling pathway Process
| Method | What It Measures | Typical Application |
|---|---|---|
| RNA-seq | Global transcriptional changes | Identify SREBP target genes and lipogenic signatures |
| ChIP-seq | SREBP binding to sterol regulatory elements | Map direct SREBP target promoters |
| Western blot | SREBP cleavage and nuclear translocation | Assess pathway activation by sterol levels |
| Lipidomics | Lipid species abundance | Quantify cholesterol and fatty acid changes |
| CRISPR knockout screens | Gene essentiality and pathway modifiers | Discover novel regulators of SREBP signaling |
| Fluorescence microscopy | Subcellular localization of SREBP | Visualize ER-to-nucleus translocation |
| Co-immunoprecipitation | Protein-protein interactions (SCAP-INSIG) | Study sterol-sensing complex dynamics |
| Luciferase reporter assays | SREBP transcriptional activity | Measure promoter activity of SRE-containing genes |
Transcriptomic profiling of SREBP target genes
RNA-seq is widely used to measure global changes in gene expression upon SREBP activation or inhibition. Target genes such as HMGCR, LDLR, FASN, and SCD1 are classic readouts. In cancer models, RNA-seq can reveal SREBP-driven lipogenic signatures and identify novel target genes.
Proteomic and lipidomic analyses
Mass spectrometry-based proteomics and lipidomics quantify changes in lipid species and enzymes following SREBP pathway manipulation. These methods help link SREBP activity to specific lipid classes and metabolic fluxes. In glioblastoma, lipidomic profiling after fatostatin treatment revealed ferroptosis-related lipid peroxidation.
Imaging SREBP nuclear translocation
Fluorescence microscopy with GFP-tagged SREBP or immunofluorescence for the N-terminal fragment allows visualization of SREBP nuclear translocation in response to sterol depletion. This approach is useful for studying regulators like SCAP and INSIG in live cells.
CRISPR screens for pathway modifiers
Genome-wide CRISPR knockout or activation screens can identify novel regulators of SREBP signaling. Such screens have uncovered components of the mTORC1-Lipin-1 axis and other modulators. These unbiased approaches are powerful for discovering therapeutic targets in metabolic diseases.
How CRISPR Can Be Used to Study GO:0032933 SREBP signaling pathway
Knockout
CRISPR knockout of SREBP pathway genes such as SREBF1, SREBF2, SCAP, or INSIG1 provides definitive loss-of-function models to study their roles in lipid metabolism and disease. For example, SREBF1 knockout in hepatocellular carcinoma cells reduces lipogenesis and inhibits tumor growth. Knockout of SCAP blocks SREBP activation and cholesterol synthesis.
Point Mutation
CRISPR point mutation allows precise modification of key residues, such as those in the sterol-sensing domain of SCAP or phosphorylation sites in Lipin-1. These models help dissect the molecular mechanisms of sterol sensing and signal transduction without altering protein expression levels.
Knock-in
Knock-in of tagged SREBP (e.g., GFP or HA) enables live-cell imaging and biochemical tracking of SREBP processing and nuclear translocation. This approach is valuable for studying dynamic regulation of the pathway in response to sterols or drugs.
Overexpression
CRISPR-mediated overexpression of constitutively active SREBP or its target genes can model hyperactive lipogenesis and disease states. For instance, overexpression of SREBP-2 in hepatic cells increases cholesterol accumulation and LDL receptor expression. Such models are useful for drug screening and mechanistic studies.
How EDITGENE Supports SREBP signaling pathway Research
Researchers studying SREBP signaling pathway-related genes often need to determine whether a candidate gene is causally involved in lipid metabolism, metabolic disease, or cancer. Precise genetic models are essential to move from correlation to causation. EDITGENE provides a comprehensive suite of CRISPR services to accelerate this research.
Contact EDITGENE today to design your custom CRISPR model for SREBP signaling pathway research.
Related Products
| Product name | Cat.No. | Species | Gene ID | |
|---|---|---|---|---|
| SREBF2 Knockout HEK293 Cell Line | EDJ-KQ1125 | Human | 6721 | Details Get a Quote |
| SREBF1 Knockout HEK293 Cell Line | EDJ-KQ1869 | Human | 6720 | Details Get a Quote |
| SCAP Knockout HEK293 Cell Line | EDJ-KQ3113 | Human | 22937 | Details Get a Quote |
| INSIG1 Knockout HEK293 Cell Line | EDJ-KQ4999 | Human | 3638 | Details Get a Quote |
| ERLIN1 Knockout HEK293 Cell Line | EDJ-KQ7109 | Human | 10613 | Details Get a Quote |
| ERLIN2 Knockout HEK293 Cell Line | EDJ-KQ7308 | Human | 11160 | Details Get a Quote |
| INSIG2 Knockout HEK293 Cell Line | EDJ-KQ10942 | Human | 51141 | Details Get a Quote |
| ARHGEF10L Knockout HEK293 Cell Line | EDJ-KQ12414 | Human | 55160 | Details Get a Quote |
| ERLIN2 Knockout A-549 Cell Line | EDJ-KQ30986 | Human | 11160 | Details Get a Quote |
| ERLIN1 Knockout A-549 Cell Line | EDJ-KQ31971 | Human | 10613 | Details Get a Quote |
| ERLIN1 Knockout HCT 116 Cell Line | EDJ-KQ31972 | Human | 10613 | Details Get a Quote |
| ERLIN1 Knockout HeLa Cell Line | EDJ-KQ31973 | Human | 10613 | Details Get a Quote |
| ARHGEF10L Knockout A-549 Cell Line | EDJ-KQ41317 | Human | 55160 | Details Get a Quote |
| ARHGEF10L Knockout HCT 116 Cell Line | EDJ-KQ41318 | Human | 55160 | Details Get a Quote |
| ARHGEF10L Knockout HeLa Cell Line | EDJ-KQ41319 | Human | 55160 | Details Get a Quote |
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Frequently Asked Questions About SREBP signaling pathway
What is the SREBP signaling pathway?
The SREBP signaling pathway (GO:0032933) is a biological process that senses decreased sterol levels in the endoplasmic reticulum and activates sterol regulatory element-binding proteins (SREBPs) to up-regulate genes involved in lipid synthesis and uptake.
What genes are involved in SREBP signaling?
Key genes include SREBF1, SREBF2, SCAP, INSIG1, INSIG2, MBTPS1, MBTPS2, LPIN1, MTOR, and PRKAA1, among others.
How is SREBP signaling regulated by mTORC1?
mTORC1 promotes SREBP activation by phosphorylating and inhibiting Lipin-1, which otherwise suppresses SREBP nuclear entry.
What diseases are associated with SREBP signaling?
Dysregulated SREBP signaling is linked to nonalcoholic fatty liver disease, hepatocellular carcinoma, atherosclerosis, type 2 diabetes, and diabetic kidney disease.
How can CRISPR be used to study SREBP signaling?
CRISPR knockout, point mutation, knock-in, and overexpression models allow precise manipulation of SREBP pathway genes to study their roles in lipid metabolism and disease.
What is the role of SREBP-1 in cancer?
SREBP-1 is often overexpressed in cancers such as hepatocellular carcinoma, where it drives lipogenesis to support tumor growth and survival.
Can SREBP signaling be targeted therapeutically?
Yes, inhibitors like fatostatin and mitochondria-targeted hydrogen sulfide donors modulate SREBP activity and show efficacy in preclinical models of cancer and fatty liver disease.
What is the connection between SREBP and ferroptosis?
In glioblastoma, inhibition of SREBP by fatostatin induces ferroptosis through the AKT/mTORC1/GPX4 pathway, linking lipid metabolism to cell death.
How does AMPK affect SREBP signaling?
AMPK activation inhibits SREBP and reduces lipogenesis under energy stress, as shown in models of diabetic kidney disease.
What methods are used to study SREBP signaling?
Common methods include RNA-seq, ChIP-seq, Western blot, lipidomics, CRISPR screens, and fluorescence microscopy to assess SREBP activation and target gene expression.
Conclusion
The SREBP signaling pathway (GO:0032933) is a central regulator of lipid homeostasis, translating sterol status into transcriptional programs that control cholesterol and fatty acid synthesis. Its dysregulation is implicated in prevalent metabolic diseases and cancers, making it a prime therapeutic target. Advances in CRISPR gene editing now enable precise dissection of pathway components, from knockouts to point mutations, accelerating the development of targeted therapies. Continued research into SREBP signaling will likely yield new insights into metabolic control and disease intervention.
References
- 1. Panwar V et al.. 2023. Multifaceted role of mTOR (mammalian target of rapamycin) signaling pathway in human health and disease.. Signal Transduct Target Ther 8(1):375 PMID: 37779156
- 2. Peterson TR et al.. 2011. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway.. Cell 146(3):408-20 PMID: 21816276
- 3. Cai J et al.. 2023. Fatostatin induces ferroptosis through inhibition of the AKT/mTORC1/GPX4 signaling pathway in glioblastoma.. Cell Death Dis 14(3):211 PMID: 36966152
- 4. Su F et al.. 2024. Regulation and targeting of SREBP-1 in hepatocellular carcinoma.. Cancer Metastasis Rev 43(2):673-708 PMID: 38036934
- 5. Shimano H et al.. 2017. SREBP-regulated lipid metabolism: convergent physiology - divergent pathophysiology.. Nat Rev Endocrinol 13(12):710-730 PMID: 28849786
- 6. Stachowicz A et al.. 2024. Mitochondria-targeted hydrogen sulfide donor reduces fatty liver and obesity in mice fed a high fat diet by inhibiting de novo lipogenesis and inflammation via mTOR/SREBP-1 and NF-κB signaling pathways.. Pharmacol Res 209:107428 PMID: 39303773
- 7. Tao J et al.. 2025. FTZ alleviates lipid deposition in diabetic kidney disease by AMPK/ACC/SREBP signaling pathway.. Acta Diabetol 62(10):1621-1630 PMID: 40167639
- 8. Romani P et al.. 2019. Extracellular matrix mechanical cues regulate lipid metabolism through Lipin-1 and SREBP.. Nat Cell Biol 21(3):338-347 PMID: 30718857
