ArticleProceedings of the National Academy of Sciences of the United States of America2002
The hypocholesterolemic agent LY295427 up-regulates INSIG-1, identifying the INSIG-1 protein as a mediator of cholesterol homeostasis through SREBP.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2002. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 78 citations in OpenAlex.
- The compound LY295427 antagonizes 25-hydroxycholesterol through binding to INSIG.Journal of lipid research · 2026Article
- Article
- Early Transcriptomic Response to OxLDL in Human Retinal Pigment Epithelial Cells.International journal of molecular sciences · 2020Article
- Protein arginine methyltransferase 5 promotes cholesterol biosynthesis-mediated Th17 responses and autoimmunity.The Journal of clinical investigation · 2020Article
- Hypolipidemic effect of Alisma orientale (Sam.) Juzep on gut microecology and liver transcriptome in diabetic rats.PloS one · 2020Article
- Membrane cholesterol as regulator of human rhomboid protease RHBDL4.The Journal of biological chemistry · 2018Article
- Genome wide association study identifies novel potential candidate genes for bovine milk cholesterol content.Scientific reports · 2018Article
- Common Genetic Variant of insig2 Gene rs7566605 Polymorphism Is Associated with Severe Obesity in North IndiaIranian biomedical journal · 2017Article
- RNA-binding protein HuD reduces triglyceride production in pancreatic β cells by enhancing the expression of insulin-induced gene 1.Biochimica et biophysica acta · 2016Article
- Side-chain oxysterols modulate cholesterol accessibility through membrane remodeling.Biochemistry · 2014Article
- Discovery of cell-type specific regulatory elements in the human genome using differential chromatin modification analysis.Nucleic acids research · 2013Article
- Differential gene expression in the adrenals of normal and anencephalic fetuses and studies focused on the Fras-1-related extracellular matrix protein (FREM2) gene.Reproductive sciences (Thousand Oaks, Calif.) · 2011Article
- Regulation of sterol regulatory element-binding transcription factor 1a by human chorionic gonadotropin and insulin in cultured rat theca-interstitial cells.Biology of reproduction · 2009Article
- Article
- Validation of candidate causal genes for obesity that affect shared metabolic pathways and networks.Nature genetics · 2009Article
- Peroxisome deficiency causes a complex phenotype because of hepatic SREBP/Insig dysregulation associated with endoplasmic reticulum stress.The Journal of biological chemistry · 2009Article
- Transcriptional profiling of the effects of 25-hydroxycholesterol on human hepatocyte metabolism and the antiviral state it conveys against the hepatitis C virus.BMC chemical biology · 2009Article
- Identification of novel genes and pathways regulating SREBP transcriptional activity.PloS one · 2009Article
- Effects of atherogenic diet and atorvastatin treatment on gene expression profiles in the C57BL/6J mouse liver.Gene expression · 2008Article
- Cholesterol: from feeding to gene regulation.Genes & nutrition · 2007Article
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1 author at 1 institution in 1 country.
Funding
Abstract
Oxysterols regulate cholesterol homeostasis through liver X receptor (LXR; cholesterol-lowering)- and sterol regulatory element-binding protein (SREBP; cholesterol-raising)-mediated signaling pathways. Previously we reported that the hypocholesterolemic agent LY295427 (4alpha-allylcholestan-3alpha-ol) reverses oxysterol-mediated suppression of SREBP processing. We now report that LY295427 increases expression of insulin-induced gene-1 (INSIG-1) and restores SREBP processing in cells treated with oxysterols. In cells overexpressing the INSIG-1 gene, by contrast, SREBP processing is suppressed and oxysterol regulation is disrupted. SREBP processing is not restored by addition of LY295427, but is restored by increasing the levels of SREBP cleavage-activating protein (SCAP). These findings suggest that the INSIG-1 protein alters sterol balance by modulating SREBP processing jointly with SCAP. To test whether the action of oxysterols on SREBP processing is mediated through endogenous INSIG-1 protein, we used RNAi to lower the expression of the INSIG-1 gene, and found that reduced INSIG-1 protein levels caused the loss of SREBP regulation by oxysterols. We conclude that: (i) INSIG-1 gene expression is suppressed by oxysterols; (ii) LY295427 treatment counters the suppressive effects of oxysterols on SREBP processing, resulting in the expression of the INSIG-1 gene; and (iii) INSIG-1 gene expression affects SREBP processing. Taken together, these data suggest that INSIG-1 plays a critical role in regulating cholesterol concentrations in the cell.
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