Anti-hyperlipidemic properties of CM108 (a flavone derivative) in vitro and in vivo.
Peroxisome proliferator-activated receptors (PPARs) and liver X receptor alpha are ligand-activated transcription factors that belong to nuclear receptors superfamily and are involved in the regulation of lipid metabolism. PPAR, especially PPAR-alpha, PPAR-gamma agonists and liver X receptor alpha agonists can regulate the expression or biosynthesis of some factors involved in the formation and function of HDL, such as apolipoprotein (apo) A-I and ATP binding cassette transporter A1 (ABCA1). It is well known that HDL plays an important role in the treatment of hyperlipidemia as the carrier of reverse cholesterol transport. In the present study, the anti-hyperlipidemic properties of CM108, a derivative of flavone, 9-Hydroxy-2-mercapto-6-phenyl-2-thioxo-1,3,5-trioxa-2lambda(5)-phospha-cyclopenta[b]naphthalen-8-one, were studied. Through the transactivation assays of in vitro study, it was discovered that CM108 could activate PPAR-alpha PPAR-gamma and liver X receptor alpha at 40-150 microg/ml, which subsequently resulted in activating ABCA1 promoter and enhancing apoA-I and apoA-II production, whereas reducing apoC-III production significantly. Furthermore, after in vivo study that the hyperlipidemic rats were treated with CM108 for 4 weeks, a significant increase was found in HDL cholesterol levels (26.7%, P<0.05) and a significant decrease was also noticed in triglyceride levels (26.3%, P<0.01) at 100 mg/kg CM108 group compared with that of control animals. Meanwhile, the atherogenicity index, represented by total cholesterol/HDL ratio, was significantly reduced (P<0.01). In conclusion, CM108 can effectively elevate HDL levels and lower triglyceride levels in hyperlipidemic rats maybe by regulating a series of genes, receptors and proteins related to HDL.
Guo
Lei
L
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai 200237, China. glei77@sohu.com
Hu
Wei-Rong
WR
Lian
Ji-Hong
JH
Ji
Wei
W
Deng
Ting
T
Qian
Ming
M
Gong
Bang-Qiang
BQ
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000235:genetics; D000818:Animals; D001053:Apolipoproteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000819:agonists / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D047309:Flavones / Q000494:pharmacology* / Q000627:therapeutic use; D017930:Genes, Reporter; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D008055:Lipids / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D000071518:Liver X Receptors; D008156:Luciferases; D008297:Male; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha / Q000819:agonists / Q000235:genetics; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000235:genetics; D013997:Time Factors; D015533:Transcriptional Activation / Q000187:drug effects*; D014162:Transfection
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D001053:Apolipoproteins; C516924:CM108; D004268:DNA-Binding Proteins; D047309:Flavones; D000960:Hypolipidemic Agents; D008055:Lipids; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605215:Nr1h3 protein, rat; D057093:Orphan Nuclear Receptors; D047493:PPAR alpha; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; D008156:Luciferases