Hypolipidemic activity and mechanism of purified herbal extract of Salvia miltiorrhiza in hyperlipidemic rats.
OBJECTIVE
The study aimed at evaluating the hypolipidemic effects of Purified Salvia miltiorrhiza extract (PSME) and investigating the potential molecular mechanisms by which PSME modulated lipid profiles in hyperlipidemic rats.


METHODS
Sprague-Dawley male rats on a high-fat/high-cholesterol diet were treated orally with PSME, GW3965 (a selective liver X receptor agonist) or vehicle alone. Gene expression analysis and transactivation assays were used to clarify the molecular mechanisms of action of PSME.


RESULTS
The concentrations of plasma total cholesterol, low-density lipoprotein cholesterol (LDL-cholesterol) and triglycerides in rats treated with PSME at 150 mg kg day(-1) were significantly decreased (P < 0.01), accompanied with significantly decreased concentrations of liver total cholesterol and triglycerides (P < 0.01). In both drug-treated rats, the concentration of high-density lipoprotein cholesterol (HDL-cholesterol) was significantly elevated (P < 0.01). Intriguingly, short heterodimer partner (SHP) mRNA level was significantly higher in PSME-treated rats (P < 0.01), accompanied with the significantly decreased mRNA level of sterol regulatory element binding protein 1c (SREBP1c) (P < 0.01), which contributed to the decreases of liver and plasma triglycerides through a farnesoid X receptor-SHP-SREBP1c pathway. ATP-binding Cassette Transporter B11 (ABCB11) and murine Mdr2 P-glycoprotein (also known as ABCB4) were significantly induced by PSME, which were responsible for biliary cholesterol solubility by proper biliary secretion of bile salts and phospholipids. The transactivation assays were used to identify PSME as a farnesoid X receptor/liver X receptor alpha coagonist.


CONCLUSIONS
These results indicated that PSME as a farnesoid X receptor/liver X receptor alpha coagonist largely improved the lipid profiles in the hyperlipidemic rats.
Ji
W
W
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Road Meilong, Shanghai 200237, China. weiji1979@yahoo.com.cn
Gong
B Q
BQ
D000818:Animals; D002784:Cholesterol / Q000097:blood / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000819:agonists; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000187:drug effects; D006949:Hyperlipidemias / Q000188:drug therapy*; D000960:Hypolipidemic Agents / Q000302:isolation & purification / Q000494:pharmacology*; D000071518:Liver X Receptors; D008297:Male; D057093:Orphan Nuclear Receptors; D010936:Plant Extracts / Q000494:pharmacology*; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000187:drug effects / Q000378:metabolism; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D014157:Transcription Factors / Q000819:agonists; D015533:Transcriptional Activation / Q000187:drug effects; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D002784:Cholesterol; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004268:DNA-Binding Proteins; D000960:Hypolipidemic Agents; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D010936:Plant Extracts; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; D000099150:Receptor, Farnesoid X-Activated; C000605215:Nr1h3 protein, rat; C099713:nuclear receptor subfamily 0, group B, member 2