1: Atherosclerosis. 2004 Feb;172(2):239-46. Related Articles, Links
The hypolipidemic natural product Commiphora mukul and its component guggulsterone inhibit oxidative modification of LDL.
Wang X, Greilberger J, Ledinski G, Kager G, Paigen B, Jurgens G.
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
[email protected]
There is accumulating evidence that LDL oxidation is essential for atherogenesis, and that antioxidants that prevent this oxidation may either slow down or prevent atherogenesis. In the present study, we found that Commiphora mukul and its cholesterol-lowering component, guggulsterone, effectively inhibited LDL oxidation mediated by either catalytic copper ions, free radicals generated with the azo compound 2,2'-azobis-(2-amidinopropane)dihydrochloride (AAPH), soybean lipoxygenase enzymatically, or mouse peritoneal macrophages. This inhibition was assessed by the decrease in the following parameters describing LDL oxidation: conjugated dienes, relative electrophoretic mobility (REM), thiobarbituric acid reactive substances, lipid hydroperoxides, oxidation-specific immune epitopes as detected with a monoclonal antibody against oxidized LDL, and the accumulation of LDL derived cholesterol esters in mouse peritoneal macrophages. We concluded that C. mukul and its lipid-lowering component, guggulsterone, significantly inhibit LDL oxidation. The combination of antioxidant and lipid-lowering properties of C. mukul and guggulsterone makes them especially beneficial against atherogenesis.
PMID: 15019533 [PubMed - indexed for MEDLINE
1: Biochem Biophys Res Commun. 2003 Apr 25;304(1):191-5. Related Articles, Links
Guggulsterone antagonizes farnesoid X receptor induction of bile salt export pump but activates pregnane X receptor to inhibit cholesterol 7alpha-hydroxylase gene.
Owsley E, Chiang JY.
Department of Biochemistry and Molecular Pathology, Northeastern Ohio Univ's College of Medicine, Rootstown, OH 44272, USA.
Bile acids activate a nuclear receptor, farnesoid X receptor (FXR), that induces bile salt export pump (BSEP) but inhibits cholesterol 7alpha-hydroxylase (CYP7A1) gene transcription in the liver. Guggulsterone, a plant sterol that lowers serum cholesterol, has been shown to antagonize FXR activated genes. Transient transfection assay of a human BSEP/luciferase reporter in HepG2 cells transfected with FXR reveals that guggulsterone strongly antagonizes bile acid induction of the BSEP gene. On the other hand, guggulsterone has no effect on FXR inhibition of the CYP7A1 gene, but strongly inhibits the human CYP7A1 gene by activation of pregnane X receptor (PXR). These results suggest that guggulsterone inhibits bile acid secretion from hepatocytes into bile and activates PXR to inhibit bile acid synthesis in the liver. Reduced conversion of cholesterol and bile acid excretion may lead to an increase of hepatic cholesterol and decrease of intestinal cholesterol absorption, and results in lowering serum cholesterol.
PMID: 12705905 [PubMed - indexed for MEDLINE]
1: Annu Rev Nutr. 2003;23:303-13. Epub 2003 Feb 26. Related Articles, Links
GUGULIPID: a natural cholesterol-lowering agent.
Urizar NL, Moore DD.
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
[email protected]
The resin of the Commiphora mukul tree has been used in Ayurvedic medicine for more than 2000 years to treat a variety of ailments. Studies in both animal models and humans have shown that this resin, termed gum guggul, can decrease elevated lipid levels. The stereoisomers E- and Z-guggulsterone have been identified as the active agents in this resin. Recent studies have shown that these compounds are antagonist ligands for the bile acid receptor farnesoid X receptor (FXR), which is an important regulator of cholesterol homeostasis. It is likely that this effect accounts for the hypolipidemic activity of these phytosteroids.
Publication Types:
Review
PMID: 12626688 [PubMed - indexed for MEDLINE]
1: Mol Pharmacol. 2005 Mar;67(3):948-54. Epub 2004 Dec 15. Related Articles, Links
The hypolipidemic natural product guggulsterone is a promiscuous steroid receptor ligand.
Burris TP, Montrose C, Houck KA, Osborne HE, Bocchinfuso WP, Yaden BC, Cheng CC, Zink RW, Barr RJ, Hepler CD, Krishnan V, Bullock HA, Burris LL, Galvin RJ, Bramlett K, Stayrook KR.
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.
[email protected]
Guggulsterone (GS) is the active substance in guggulipid, an extract of the guggul tree, Commiphora mukul, used to treat a variety of disorders in humans, including dyslipidemia, obesity, and inflammation. The activity of GS has been suggested to be mediated by antagonism of the receptor for bile acids, the farnesoid X receptor (FXR). Here, we demonstrate that both stereoisomers of the plant sterol, (E)- and (Z)-GS, bind to the steroid receptors at a much higher affinity than to FXR. Both stereoisomers bind to the mineralocorticoid receptor (MR) with a Ki value of approximately 35 nM, which is greater than 100 times more potent than their affinity for FXR. Both (E)- and (Z)-GS also displayed high affinity for other steroid receptors, including the androgen (AR), glucocorticoid (GR), and progesterone receptors (PR) with Ki values ranging from 224 to 315 nM. In cell-based functional cotransfection assays, GSs behaved as antagonists of AR, GR, and MR, but as agonists of PR. Agonist activity was also demonstrated with estrogen receptor (ER) alpha; however, the potency was very low (EC50 > 5000 nM). In addition, GS displayed activity in functional assays in cell lines expressing endogenous AR, GR, ER, and PR.
These data suggest that the variety of pharmacological effects exhibited by GS may be mediated by targeting several steroid receptors.
PMID: 15602004 [PubMed - indexed for MEDLINE
.gif "IP Gear")
