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Rohitukine inhibits in vitro adipogenesis arresting mitotic clonal expansion and improves dyslipidemia in vivo.
- Source :
-
Journal of lipid research [J Lipid Res] 2014 Jun; Vol. 55 (6), pp. 1019-32. Date of Electronic Publication: 2014 Mar 19. - Publication Year :
- 2014
-
Abstract
- We developed a common feature pharmacophore model using known antiadipogenic compounds (CFPMA). We identified rohitukine, a reported chromone anticancer alkaloid as a potential hit through in silico mapping of the in-house natural product library on CFPMA. Studies were designed to assess the antiadipogenic potential of rohitukine. Rohitukine was isolated from Dysoxylum binacteriferum Hook. to ⬧95% purity. As predicted by CFPMA, rohitukine was indeed found to be an antiadipogenic molecule. Rohitukine inhibited lipid accumulation and adipogenic differentiation in a concentration- and exposure-time-dependent manner in 3T3-L1 and C3H10T1/2 cells. Rohitukine downregulated expression of PPARγ, CCAAT/enhancer binding protein α, adipocyte protein 2 (aP2), FAS, and glucose transporter 4. It also suppressed mRNA expression of LPL, sterol-regulatory element binding protein (SREBP) 1c, FAS, and aP2, the downstream targets of PPARγ. Rohitukine arrests cells in S phase during mitotic clonal expansion. Rohitukine was bioavailable, and 25.7% of orally administered compound reached systemic circulation. We evaluated the effect of rohitukine on dyslipidemia induced by high-fat diet in the hamster model. Rohitukine increased hepatic expression of liver X receptor α and decreased expression of SREBP-2 and associated targets. Rohitukine decreased hepatic and gonadal lipid accumulation and ameliorated dyslipidemia significantly. In summary, our strategy to identify a novel antiadipogenic molecule using CFPMA successfully resulted in identification of rohitukine, which confirmed antiadipogenic activity and also exhibited in vivo antidyslipidemic activity.<br /> (Copyright © 2014 by the American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- 3T3-L1 Cells
Animals
Chromones chemistry
Dyslipidemias metabolism
Dyslipidemias pathology
Female
Male
Mesocricetus
Mice
Piperidines chemistry
Adipogenesis drug effects
Chromones pharmacology
Dyslipidemias drug therapy
Mitosis drug effects
Piperidines pharmacology
S Phase Cell Cycle Checkpoints drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1539-7262
- Volume :
- 55
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Journal of lipid research
- Publication Type :
- Academic Journal
- Accession number :
- 24646949
- Full Text :
- https://doi.org/10.1194/jlr.M039925