ArticleJournal of lipid research2019
Endogenous sterol intermediates of the mevalonate pathway regulate HMGCR degradation and SREBP-2 processing.
Article in Journal of lipid research, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 98 citations in OpenAlex.
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- Sterol biosynthesis, brain development, and disease.The Journal of clinical investigation · 2026Review
- Impaired cortical actin dynamics via lanosterol-dependent HMG-CoA reductase downregulation mediates IFN-α-induced mast cell stabilization.The Journal of biological chemistry · 2026Article
- Emerging roles of the metabolic regulator 3-hydroxy-3-methylglutaryl coenzyme-CoA reductase in human cancers: From biology to therapeutics.Genes & diseases · 2026Review
- Statins targeting mevalonate-geranylgeranyl diphosphate pathway inhibit proliferation in NK/T lymphoma by promoting pyroptosis.Translational oncology · 2026Article
- Chronic PFOA and PFOS exposure triggers cellular oxidative stress and alters lipid levels as revealed through multi-omics analysis.Environmental science. Advances · 2026Article
- The compound LY295427 antagonizes 25-hydroxycholesterol through binding to INSIG.Journal of lipid research · 2026Article
- Dietary mixed-oxysterols and 27-Hydroxycholesterol induce cognitive impairment by regulating gut microbiota and miR-144-3p in vivo.GeroScience · 2026Article
- Systems pharmacology approaches decipher the anti-cancer efficacy of ethnopharmacological agents in hepatocellular carcinoma.Scientific reports · 2025Article
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- COVID-19 and dysregulated cholesterol levels in Type I and Type II diabetes: focus on the difference.Biologia futura · 2025Review
- Cholesterol metabolism: molecular mechanisms, biological functions, diseases, and therapeutic targets.Molecular biomedicine · 2025Review
- Bacteroides sphingolipids promote anti-inflammatory responses through the mevalonate pathway.Cell host & microbe · 2025Article
- Cholesterol and SREBP2 Dynamics During Spermatogenesis Stages in Rabbits: Effects of High-Fat Diet and Protective Role of Extra Virgin Olive Oil.International journal of molecular sciences · 2025Article
- Ablation of Hepatic Asah1 Gene Disrupts Hepatic Lipid Homeostasis and Promotes Fibrotic Nonalcoholic Steatohepatitis in Mice.The American journal of pathology · 2025Article
- An endothelial SOX18-mevalonate pathway axis enables repurposing of statins for infantile hemangioma.The Journal of clinical investigation · 2025Article
- Knockouts ofiScience · 2024Article
- Identification of Potential New Genes Related to the SREBP Pathway inBiomolecules · 2024Article
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Authors and funding
11 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Sterol-regulated HMG-CoA reductase (HMGCR) degradation and SREBP-2 cleavage are two major feedback regulatory mechanisms governing cholesterol biosynthesis. Reportedly, lanosterol selectively stimulates HMGCR degradation, and cholesterol is a specific regulator of SREBP-2 cleavage. However, it is unclear whether other endogenously generated sterols regulate these events. Here, we investigated the sterol intermediates from the mevalonate pathway of cholesterol biosynthesis using a CRISPR/Cas9-mediated genetic engineering approach. With a constructed HeLa cell line expressing the mevalonate transporter, we individually deleted genes encoding major enzymes in the mevalonate pathway, used lipidomics to measure sterol intermediates, and examined HMGCR and SREBP-2 statuses. We found that the C4-dimethylated sterol intermediates, including lanosterol, 24,25-dihydrolanosterol, follicular fluid meiosis activating sterol, testis meiosis activating sterol, and dihydro-testis meiosis activating sterol, were significantly upregulated upon mevalonate loading. These intermediates augmented both degradation of HMGCR and inhibition of SREBP-2 cleavage. The accumulated lanosterol induced rapid degradation of HMGCR, but did not inhibit SREBP-2 cleavage. The newly synthesized cholesterol from the mevalonate pathway is dispensable for inhibiting SREBP-2 cleavage. Together, these results suggest that lanosterol is a bona fide endogenous regulator that specifically promotes HMGCR degradation, and that other C4-dimethylated sterol intermediates may regulate both HMGCR degradation and SREBP-2 cleavage.
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