Chen, Liang; Ma, Mei-Yan; Sun, Ming; Jiang, Lu-Yi; Zhao, Xue-Tong; Fang, Xian-Xiu; Lam, Sin Man; Shui, Guang-Hou; Luo, Jie; Shi, Xiong-Jie; Song, Bao-Liang published the artcile< Endogenous sterol intermediates of the mevalonate pathway regulate HMGCR degradation and SREBP-2 processing>, Safety of (3S,9S,10R,13R,14R,17R)-10,13-Dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol, the main research area is sterol HMGCR SREBP2 CYP51A1 signaling cervical cancer; 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation; clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9); lanosterol; mevalonate; sterol intermediates; sterol regulatory element-binding protein-2; sterol regulatory element-binding protein-2 cleavage.
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.
Journal of Lipid Research published new progress about Homo sapiens Role: BSU (Biological Study, Unclassified), BIOL (Biological Study). 434-16-2 belongs to class alcohols-buliding-blocks, and the molecular formula is C27H44O, Safety of (3S,9S,10R,13R,14R,17R)-10,13-Dimethyl-17-((R)-6-methylheptan-2-yl)-2,3,4,9,10,11,12,13,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-ol.
Referemce:
Alcohol – Wikipedia,
Alcohols – Chemistry LibreTexts