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GeneE
10 sources retrieved · Most recent: April 2026 · Index updated 15 days ago
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INSIG2
insulin induced gene 2
Chromosome 2 · 2q14.1-q14.2
NCBI Gene: 51141Ensembl: ENSG00000125629.17HGNC: HGNC:20452UniProt: B4DQ23
118PubMed Papers
20Diseases
0Drugs
0Pathogenic Variants
DATA QUALITY
✓ Experimental GO Evidence✓ Swiss-Prot Reviewed
protein bindingoxysterol bindingprotein sequestering activitycholesterol biosynthetic processHypercholesterolemiametabolic diseaseresponse to statinhyperlipidemia
✦AI Summary

INSIG2 is an oxysterol-binding protein that functions as a master negative regulator of cholesterol synthesis through dual mechanisms 1. Structurally, INSIG2 binds oxysterols (including 25-hydroxycholesterol) in the endoplasmic reticulum (ER) membrane and uses this binding to retain the SCAP-SREBP complex at the ER, preventing SREBP transcription factors from translocating to the Golgi for activation 2. Under sterol deprivation or upon phosphorylation by PCK1, INSIG2-oxysterol binding weakens, allowing SCAP-SREBP release and lipogenic gene activation 1. Additionally, INSIG2 mediates degradation of HMG-CoA reductase (HMGCR) via ER-associated degradation, further suppressing cholesterol synthesis 3. Disease relevance is substantial: CD36 overexpression in hepatocytes disrupts CD36-INSIG2 interaction, promoting SREBP1 processing and hepatic steatosis in NAFLD 4. Tumor-derived exosomal miR-9-5p downregulates INSIG2 in liver, enhancing cholesterol synthesis and promoting metastatic progression 5. In diabetic kidney disease, HSPA8 dysfunction leads to excessive INSIG2 phosphorylation and SREBP activation, promoting lipid accumulation 6. Clinically, INSIG2 polymorphisms associate with elevated triglycerides and blood pressure in obese patients 7, and minor intron splicing defects causing INSIG1/2 truncation drive metabolic dysfunction-associated steatotic liver disease progression 8.

Sources cited
1
PCK1 phosphorylation of INSIG2 at Ser151 reduces sterol binding and disrupts INSIG-SCAP interaction, activating SREBP and lipogenesis in cancer
PMID: 32322062
2
Structural basis showing 25-hydroxycholesterol sandwiched between Scap and Insig-2 transmembrane domains regulates their interaction
PMID: 33446483
3
INSIG2 mediates sterol-induced ER-associated degradation of HMGCR
PMID: 16606821
4
CD36 forms a complex with INSIG2 that disrupts SCAP-INSIG2 interaction, promoting SREBP1 processing and DNL in hepatocytes
PMID: 34974159
5
Tumor-derived miR-9-5p targets INSIG2, upregulating HMGCR and promoting breast cancer liver metastasis
PMID: 39627188
6
HSPA8 reduces PKR-mediated INSIG phosphorylation, suppressing SREBP activation in diabetic kidney disease
PMID: 39977267
7
INSIG2 rs75666605 polymorphism associates with higher triglycerides and blood pressure in obese subjects
PMID: 31144980
8
Minor intron retention in INSIG1/2 causes premature translation termination, driving SREBP1c activation in metabolic dysfunction-associated steatotic liver disease
PMID: 40100939
Disease Associationsⓘ20
HypercholesterolemiaOpen Targets
0.45Moderate
metabolic diseaseOpen Targets
0.44Moderate
response to statinOpen Targets
0.41Moderate
hyperlipidemiaOpen Targets
0.38Weak
Varicose veinsOpen Targets
0.38Weak
neurodegenerative diseaseOpen Targets
0.34Weak
skull disorderOpen Targets
0.31Weak
vein disorderOpen Targets
0.29Weak
alcohol drinkingOpen Targets
0.27Weak
familial hypercholesterolemiaOpen Targets
0.21Weak
femoral neck fractureOpen Targets
0.19Weak
Abnormality of the skeletal systemOpen Targets
0.19Weak
hidradenitisOpen Targets
0.18Weak
Disorder of lipid metabolismOpen Targets
0.18Weak
lymphatic system diseaseOpen Targets
0.18Weak
muscular atrophyOpen Targets
0.17Weak
facial morphologyOpen Targets
0.13Weak
Chorioretinal scarOpen Targets
0.13Weak
duodenitisOpen Targets
0.13Weak
vascular diseaseOpen Targets
0.13Weak
Pathogenic Variants
No pathogenic variants reported on ClinVar for this gene.
View on ClinVar ↗
Related Genes
HMGCRProtein interaction99%AMFRProtein interaction95%RNF139Protein interaction84%GPR85Protein interaction78%MLXIPLProtein interaction77%RNF145Protein interaction74%
Tissue Expression6 tissues
Liver
100%
Brain
55%
Heart
55%
Lung
50%
Ovary
41%
Bone Marrow
18%
Gene Interaction Network
Click a node to explore
INSIG2HMGCRAMFRRNF139GPR85MLXIPLRNF145
PROTEIN STRUCTURE
Preparing viewer…
PDB4J82 · 1.46 Å · X-ray
View on RCSB ↗
Constraintⓘ
LOEUFⓘ
0.63LoF Tolerant
pLIⓘ
0.77Intermediate
Observed/Expected LoF0.33 [0.19–0.63]
RankingsWhere INSIG2 stands among ~20K protein-coding genes
  • #3,995of 20,598
    Most Researched118 · top quartile
  • #4,405of 17,882
    Most Constrained (LOEUF)0.63 · top quartile
Genes detectedINSIG2
Sources retrieved10 papers
Response time—
📄 Sources
10▼
1
The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis.
PMID: 32322062
Nature · 2020
1.00
2
Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis.
PMID: 38438089
Pharmacol Res · 2024
0.90
3
CD36 promotes de novo lipogenesis in hepatocytes through INSIG2-dependent SREBP1 processing.
PMID: 34974159
Mol Metab · 2022
0.80
4
Tumor-derived miR-9-5p-loaded EVs regulate cholesterol homeostasis to promote breast cancer liver metastasis in mice.
PMID: 39627188
Nat Commun · 2024
0.70
5
HSPA8 dampens SCAP/INSIG split and SREBP activation by reducing PKR-mediated INSIG phosphorylation.
PMID: 39977267
Cell Rep · 2025
0.60