Hypolipidemic agent Z-guggulsterone: metabolism interplays with induction of carboxylesterase and bile salt export pump

Abstract

Z-Guggulsterone is a major ingredient in the Indian traditional hypolipidemic remedy guggul. A study in mice has established that its hypolipidemic effect involves the farnesoid X receptor (FXR), presumably by acting as an antagonist of this receptor. It is generally assumed that the antagonism leads to induction of cytochrome P450 7A1 (CYP7A1), the rate-limiting enzyme converting free cholesterol to bile acids. In this study, we tested whether Z-guggulsterone indeed induces human CYP7A1. In addition, the expression of cholesteryl ester hydrolase CES1 and bile salt export pump (BSEP) was monitored. Contrary to the general assumption, Z-guggulsterone did not induce CYP7A1. Instead, this phytosterol significantly induced CES1 and BSEP through transactivation. Z-Guggulsterone underwent metabolism by CYP3A4, and the metabolites greatly increased the induction potency on BSEP but not on CES1. BSEP induction favors cholesterol elimination, whereas CES1 involves both elimination and retention (probably when excessively induced). Interestingly, clinical trials reported the hypolipidemic response rates from 18% to 80% and showed that higher dosages actually increased VLDL cholesterol. Our findings predict that better hypolipidemic outcomes likely occur in individuals who have a relatively higher capacity of metabolizing Z-guggulsterone with moderate CES1 induction, a scenario possibly achieved by lowering the dosing regimens. Z-Guggulsterone is a major ingredient in the Indian traditional hypolipidemic remedy guggul. A study in mice has established that its hypolipidemic effect involves the farnesoid X receptor (FXR), presumably by acting as an antagonist of this receptor. It is generally assumed that the antagonism leads to induction of cytochrome P450 7A1 (CYP7A1), the rate-limiting enzyme converting free cholesterol to bile acids. In this study, we tested whether Z-guggulsterone indeed induces human CYP7A1. In addition, the expression of cholesteryl ester hydrolase CES1 and bile salt export pump (BSEP) was monitored. Contrary to the general assumption, Z-guggulsterone did not induce CYP7A1. Instead, this phytosterol significantly induced CES1 and BSEP through transactivation. Z-Guggulsterone underwent metabolism by CYP3A4, and the metabolites greatly increased the induction potency on BSEP but not on CES1. BSEP induction favors cholesterol elimination, whereas CES1 involves both elimination and retention (probably when excessively induced). Interestingly, clinical trials reported the hypolipidemic response rates from 18% to 80% and showed that higher dosages actually increased VLDL cholesterol. Our findings predict that better hypolipidemic outcomes likely occur in individuals who have a relatively higher capacity of metabolizing Z-guggulsterone with moderate CES1 induction, a scenario possibly achieved by lowering the dosing regimens. Cardiovascular diseases remain the leading cause of death. The majority of these diseases involve a pathogenic process: atherosclerosis (1Buemi M. Aloisi C. Fulvio F. Caccamo C. Cavallaro E. Crascì E. Criseo M. Corica F. Frisina N. Cardiorenal consequences of atherosclerosis and statins therapy: from the past to the future.Curr. Pharm. Des. 2005; 11: 3973-3984Crossref PubMed Scopus (9) Google Scholar). Hyperlipidemia is the primary atherogenic risk factor (1Buemi M. Aloisi C. Fulvio F. Caccamo C. Cavallaro E. Crascì E. Criseo M. Corica F. Frisina N. Cardiorenal consequences of atherosclerosis and statins therapy: from the past to the future.Curr. Pharm. Des. 2005; 11: 3973-3984Crossref PubMed Scopus (9) Google Scholar, 2Sundaram M. Yao Z. Recent progress in understanding protein and lipid factors affecting hepatic VLDL assembly and secretion.Nutr. Metab. (Lond). 2010; 7: 35Crossref PubMed Scopus (120) Google Scholar). In the plasma, lipids are encapsulated particles with apoproteins (1Buemi M. Aloisi C. Fulvio F. Caccamo C. Cavallaro E. Crascì E. Criseo M. Corica F. Frisina N. Cardiorenal consequences of atherosclerosis and statins therapy: from the past to the future.Curr. Pharm. Des. 2005; 11: 3973-3984Crossref PubMed Scopus (9) Google Scholar). High-density lipoproteins (HDL) transport lipids from peripheral tissues to the liver and, thus, are antiatherogenic (1Buemi M. Aloisi C. Fulvio F. Caccamo C. Cavallaro E. Crascì E. Criseo M. Corica F. Frisina N. Cardiorenal consequences of atherosclerosis and statins therapy: from the past to the future.Curr. Pharm. Des. 2005; 11: 3973-3984Crossref PubMed Scopus (9) Google Scholar). Low-density lipoproteins (LDL) are the major type of lipoproteins accumulated in the subendothelial matrix and, hence, are atherogenic. LDL is derived from very low-density lipoproteins (VLDL), which are assembled in and secreted by the liver (2Sundaram M. Yao Z. Recent progress in understanding protein and lipid factors affecting hepatic VLDL assembly and secretion.Nutr. Metab. (Lond). 2010; 7: 35Crossref PubMed Scopus (120) Google Scholar). VLDL assembly starts when apolipoprotein B-100 (apo-B100) is translated and translocated into endoplasmic reticulum (ER). Maturation of VLDL particles undergoes multiple lipidation processes that traverse from the ER and post-ER/Golgi compartments (2Sundaram M. Yao Z. Recent progress in understanding protein and lipid factors affecting hepatic VLDL assembly and secretion.Nutr. Metab. (Lond). 2010; 7: 35Crossref PubMed Scopus (120) Google Scholar). Lipids incorporated into VLDL particles undergo continuous hydrolysis/reesterification. Carboxylesterase-1 (CES1) in humans and its functionally related mouse counterpart (Ces1d) in lipid catabolism are implicated in the hydrolysis/reesterification cycle (3Wei E. Alam M. Sun F. Agellon L.B. Vance D.E. Lehner R. Apolipoprotein B and triacylglycerol secretion in human triacylglycerol hydrolase transgenic mice.J. Lipid Res. 2007; 48: 2597-2606Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 4Wei E. Ben Ali Y. Lyon J. Wang H. Nelson R. Dolinsky V.W. Dyck J.R. Mitchell G. Korbutt G.S. Lehner R. Loss of TGH/Ces3 in mice decreases blood lipids, improves glucose tolerance, and increases energy expenditure.Cell Metab. 2010; 11: 183-193Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar). Indeed, higher CES1 activity facilitates VLDL maturation (5Blais D.R. Lyn R.K. Joyce M.A. Rouleau Y. Steenbergen R. Barsby N. Zhu L.F. Pegoraro A.F. Stolow A. Tyrrell D.L. et al.Activity-based protein profiling identifies a host enzyme, carboxylesterase 1, which is differentially active during hepatitis C virus replication.J. Biol. Chem. 2010; 285: 25602-25612Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar), and transgenic expression of CES1 leads to increased secretion of apoB proteins (3Wei E. Alam M. Sun F. Agellon L.B. Vance D.E. Lehner R. Apolipoprotein B and triacylglycerol secretion in human triacylglycerol hydrolase transgenic mice.J. Lipid Res. 2007; 48: 2597-2606Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). Conversely, hydrolysis of cholesterol esters by CES1 is linked to cholesterol elimination (6Zhao B. Natarajan R. Ghosh S. Human liver cholesteryl ester hydrolase: cloning, molecular characterization, and role in cellular cholesterol homeostasis.Physiol. Genomics. 2005; 23: 304-310Crossref PubMed Scopus (50) Google Scholar). In the classic pathway of bile acid synthesis, cholesterol is oxidized by cytochrome 7A1 (CYP7A1) (7Chiang J.Y. Bile acids: regulation of synthesis.J. Lipid Res. 2009; 50: 1955-1966Abstract Full Text Full Text PDF PubMed Scopus (1104) Google Scholar), eventually converted into bile acids, and secreted by the bile acid export pump (BSEP). The secretion of bile acids represents the net elimination of excessive cholesterol (8Dawson P.A. Lan T. Rao A. Bile acid transporters.J. Lipid Res. 2009; 50: 2340-2357Abstract Full Text Full Text PDF PubMed Scopus (499) Google Scholar). Increased bile acid synthesis has long been explored for the development of drugs with cholesterol-lowering activity. The biliary secretion has a large capacity and is equally effective in eliminating both endogenous and dietary cholesterols. For quite some time, guggul has gained interest worldwide (9Urizar N.L. Moore D.D. GUGULIPID: a natural cholesterol-lowering agent.Annu. Rev. Nutr. 2003; 23: 303-313Crossref PubMed Scopus (214) Google Scholar, 10Szapary P.O. Wolfe M.L. Bloedon L.T. Cucchiara A.J. DerMarderosian A.H. Cirigliano M.D. Rader D.J. Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial.JAMA. 2003; 290: 765-772Crossref PubMed Scopus (199) Google Scholar–11Nohr L.A. Rasmussen L.B. Straand J. Resin from the mukul myrrh tree, guggul, can it be used for treating hypercholesterolemia? A randomized, controlled study.Complement. Ther. Med. 2009; 17: 16-22Crossref PubMed Scopus (50) Google Scholar). Originally described in the Indian traditional medicine Ayurveda, guggul has been used for thousands of years to treat conditions such as atherosclerosis (9Urizar N.L. Moore D.D. GUGULIPID: a natural cholesterol-lowering agent.Annu. Rev. Nutr. 2003; 23: 303-313Crossref PubMed Scopus (214) Google Scholar, 12Deng R. Yang D. Radke A. Yang J. Yan B. The hypolipidemic agent guggulsterone regulates the expression of human bile salt export pump: dominance of transactivation over farsenoid X receptor-mediated antagonism.J. Pharmacol. Exp. Ther. 2007; 320: 1153-1162Crossref PubMed Scopus (34) Google Scholar). The hypolipidemic activity has been confirmed in multiple animal models (9Urizar N.L. Moore D.D. GUGULIPID: a natural cholesterol-lowering agent.Annu. Rev. Nutr. 2003; 23: 303-313Crossref PubMed Scopus (214) Google Scholar). Human clinical trials, however, produced inconsistent results. Some clinical trials reported that guggul lowered plasma cholesterol by 20–30% and triglycerides by with the response as as 80% (9Urizar N.L. Moore D.D. GUGULIPID: a natural cholesterol-lowering agent.Annu. Rev. Nutr. 2003; 23: 303-313Crossref PubMed Scopus (214) Google Scholar, R.K. S. M. N. of of in primary Google Scholar, S. trials with A Google Scholar). trials, however, did not the of P.O. Wolfe M.L. Bloedon L.T. Cucchiara A.J. DerMarderosian A.H. Cirigliano M.D. Rader D.J. Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial.JAMA. 2003; 290: 765-772Crossref PubMed Scopus (199) Google Scholar, L.A. Rasmussen L.B. Straand J. Resin from the mukul myrrh tree, guggul, can it be used for treating hypercholesterolemia? A randomized, controlled study.Complement. Ther. Med. 2009; 17: 16-22Crossref PubMed Scopus (50) Google Scholar). Z-guggulsterone is as the major active hypolipidemic activity in mice the farnesoid X receptor N.L. Yan Y. D.J. Moore D.D. A natural that cholesterol as an antagonist for PubMed Scopus Google Scholar). phytosterol is an antagonist of and such antagonism is assumed to bile acid synthesis by CYP7A1. this human primary with and the expression of was In addition, the expression of CES1 and BSEP was monitored. Contrary to the general assumption, Z-guggulsterone was an of CES1 and BSEP but not of CYP7A1. In addition, Z-guggulsterone was and the metabolites differentially CES1 and BSEP Our findings predict that the hypolipidemic activity of Z-guggulsterone on CES1 induction and the metabolism of Z-guggulsterone the CES1 and Human primary from the and of The of the human was by the and and with acid both as described R. Yang D. Radke A. Yang J. Yan B. The hypolipidemic agent guggulsterone regulates the expression of human bile salt export pump: dominance of transactivation over farsenoid X receptor-mediated antagonism.J. Pharmacol. Exp. Ther. 2007; 320: 1153-1162Crossref PubMed Scopus (34) Google Scholar). The with D. Wang R. Yan B. Human and and hydrolysis of and Pharmacol. 2009; PubMed Scopus Google Scholar). The and The CES1 both and and both are by T. M. T. S. M. Y. T. and of human carboxylesterase and Genomics. PubMed Scopus Google Scholar). The BSEP guggulsterone and the expression described R. Yang D. Radke A. Yang J. Yan B. 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Yan B. is by carboxylesterase human carboxylesterase 1, and the is by agent Pharmacol. Exp. Ther. PubMed Scopus Google Scholar, D. Yang D. Yan B. in expression of carboxylesterase during the a of the capacity to the PubMed Scopus Google Scholar). to conditions the Z-Guggulsterone was in and the of the was by the and for The by of the by For the the a reported T. A. N. et of cytochrome P450 a facilitates 2009; PubMed Scopus Google Scholar). The metabolism was for the of Z-guggulsterone by D. Yang D. Yan B. in expression of carboxylesterase during the a of the capacity to the PubMed Scopus Google Scholar). of the was in the of for Z-guggulsterone and for was a of to The was from to for in a of with The on a by a of acid and The with for for for for and for with the of The metabolites by a The metabolites by and the to the with Z-guggulsterone The metabolites for the by a The conditions the as described but with a as with as the and mouse from mice by a as described D. Yang D. Yan B. increases the expression of the X receptor and in the induction of cytochrome P450 Pharmacol. 2010; PubMed Scopus Google Scholar). from the liver in and by in The was in and was by The to for in a with and the was was to and the to the in the for but the was in treatment for the treatment was in for in and by as described D. Yang D. Yan B. increases the expression of the X receptor and in the induction of cytochrome P450 Pharmacol. 2010; PubMed Scopus Google Scholar). mice free to and and the of was by the and for activity was as described D. Y. Yan B. of carboxylesterase expression by a in but a in protein and PubMed Scopus Google Scholar). was with and to with a and a the for in by in the and The of by this is on the of a from and was as described D. Yang D. Yan B. increases the expression of the X receptor and in the induction of cytochrome P450 Pharmacol. 2010; PubMed Scopus Google Scholar, F. Yang D. R. Yan B. The and in the the in to the X receptor but differentially to J. PubMed Scopus Google Scholar). was D. Yang D. Yan B. in expression of carboxylesterase during the a of the capacity to the PubMed Scopus Google Scholar, D. Yang J. D. R. Yan B. transactivation of the bile salt export pump and this effect is by cytochrome P450 metabolism but by a J. Pharmacol. PubMed Scopus Google Scholar). of CES1 a was described H. E. Yan B. differentially regulates expression of carboxylesterase in humans and Metab. Google Scholar). The BSEP and was from the human from and the mouse from by by a multiple It is generally assumed that Z-guggulsterone hypolipidemic activity on a (7Chiang J.Y. Bile acids: regulation of synthesis.J. Lipid Res. 2009; 50: 1955-1966Abstract Full Text Full Text PDF PubMed Scopus (1104) Google by bile acid synthesis through CYP7A1. the with guggul did not increased expression of J. A. J. S. F. is a farnesoid X receptor antagonist in but to of bile salt export Biol. Chem. 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). we an to whether Z-guggulsterone induces human CYP7A1. Human primary with and the expression was a of E. M. A. G. A. G. C. regulation of bile acid synthesis in primary human that is the 2003; PubMed Google Scholar), was in this study as a Contrary to the general assumption, Z-guggulsterone a of the did not significantly The was by Z-guggulsterone The of protein showed a of to the of In to the of Z-guggulsterone significantly induced both CES1 and BSEP with BSEP The of induction of BSEP was higher that of CES1 in the primary with increased BSEP induction but CES1 induction with the of CES1 and BSEP proteins of to of the have that Z-guggulsterone induces BSEP through transactivation R. Yang D. Radke A. Yang J. Yan B. The hypolipidemic agent guggulsterone regulates the expression of human bile salt export pump: dominance of transactivation over farsenoid X receptor-mediated antagonism.J. Pharmacol. Exp. Ther. 2007; 320: 1153-1162Crossref PubMed Scopus (34) Google Scholar). we tested whether transactivation is in CES1 human hepatic used for this induction was in this in Z-guggulsterone induced CES1 and BSEP in a however, the of induction induced but CES1 was induced to a significantly and on CES1 induction significantly from and induction of the of the and did not and did and we tested whether a the induction of both CES1 and with Z-guggulsterone in the of D. in with the induction of both CES1 and that Z-guggulsterone induces BSEP R. Yang D. Radke A. Yang J. Yan B. The hypolipidemic agent guggulsterone regulates the expression of human bile salt export pump: dominance of transactivation over farsenoid X receptor-mediated antagonism.J. Pharmacol. Exp. Ther. 2007; 320: 1153-1162Crossref PubMed Scopus (34) Google Scholar), through transactivation. tested whether Z-guggulsterone the of the of the CES1 T. M. T. S. M. Y. T. and of human carboxylesterase and Genomics. PubMed Scopus Google Scholar). in by and The was and with the the to that this to the transactivation. the for the to the with the to Z-guggulsterone and the tested for the as a of in the was the that the CES1 a of the whereas the BSEP with from Z-guggulsterone a with the was by the In the effect described in 1, BSEP was induced higher in primary whereas CES1 was induced higher in on the is that primary higher of CES1 and, thus, the is is that primary but not A. of and The of Scholar), whether Z-guggulsterone actually undergoes with human liver in the of the is for by and A. of and The of Scholar). in the a with a retention of however, by when the was in the of the time, with a retention of and was the The majority of are by the A. of and The of Scholar). tested whether with but in the of a A of and the of and a in the metabolism whereas the used to the activity of The study that multiple with the the this tested for with the study, the activity metabolism was with and metabolism was with and and metabolism was with and Interestingly, was the active the showed activity for to the activity of whether the metabolism the induction we major we a study to the of the metabolism by in the was by of increased the The by was very to that by liver that this is the primary enzyme for the Interestingly, the produced of and however, produced this we and to in metabolites produced a with a retention that was and the metabolites Z-Guggulsterone a of an of whereas the from an of a whether the metabolites and Z-guggulsterone in the induction and The of the metabolites on the the study major metabolites which was not to the with metabolites increases in the of BSEP with the In the of in CES1 was with a a and a in CES1 induction metabolites tested showed significantly higher induction of BSEP CES1 tested the of CES1 and BSEP by The are in The in with in the induction of CES1 and BSEP metabolites showed increases in the of the which was not in induction For actually a in the induction of CES1 and metabolites generally in the of the in induction of the For higher increases in the induction of BSEP CES1 whereas this increases in the of both the in the CES1 in the induction of CES1 For with the in the induction by was whereas the in the by was whether metabolism of Z-guggulsterone differentially BSEP and CES1 induction, with the with Z-guggulsterone and for the induction of CES1 and BSEP in of CYP3A4, with the significantly increased BSEP but not CES1 whether Z-guggulsterone the expression of the mouse mouse primary with in Z-guggulsterone significantly induced but not and not by with the on the expression of BSEP and in with guggul J. 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Yan B. of carboxylesterase expression by a in but a in protein and PubMed Scopus Google Scholar). can be by in both and Z-guggulsterone induced major mouse such as and but not such as mouse counterpart of human The of some of the mouse to be Z-guggulsterone significantly increased hydrolysis by CES1 but by with the increased hydrolysis of CES1 by study has that Z-guggulsterone significantly induced CES1 and The induction of CES1 by the induction of was achieved by transactivation The transactivation on a as the guggulsterone both and BSEP guggulsterone response an a and an the is in an to that of BSEP the from that of BSEP these differentially to Z-guggulsterone and its with increased the of the BSEP from to whereas the was in the of the from to the the and induction of BSEP whereas the of CES1 was higher the induction is that the BSEP the primary for BSEP induction by whereas the represents of the for CES1 the metabolism of Z-guggulsterone is by The by human was to that by the the metabolism by an of showed of Z-guggulsterone metabolism by liver significantly this phytosterol is that Z-guggulsterone is a of both and but has higher and the In addition, is to in the liver A. of and The of Scholar). to the hepatic metabolism of was that produced metabolites of from of a In the of from of increased the of but that is a of to the metabolites generally increased the induction of both CES1 and the was on BSEP of bile acids represents net elimination of cholesterol (8Dawson P.A. Lan T. Rao A. Bile acid transporters.J. Lipid Res. 2009; 50: 2340-2357Abstract Full Text Full Text PDF PubMed Scopus (499) Google induction of BSEP favors lowering cholesterol. In induction of CES1 the elimination of on the of that the of CES1 leads to increased free of in individuals the of cholesterol into bile acids, whereas of in the pathway of VLDL in individuals with a of BSEP induction to CES1 induction (probably with capacity of metabolizing in lowering cholesterol. the metabolites likely hypolipidemic The on the is factor that the hypolipidemic The guggul in a increased the by whereas the increased it by to the excessive induction of CES1 S. trials with A Google Scholar). have that Z-guggulsterone and that of favors the induction of BSEP but not CES1 A study Z-guggulsterone as a of the X receptor The of receptor to X receptor the activity of guggulsterone the Pharmacol. Exp. Ther. 2005; PubMed Scopus Google Scholar), a receptor dosages the likely metabolites with potency on BSEP induction and, thus, better plasma lipid that Z-guggulsterone induced mouse however, it to be whether these lipid retention The of the activity significantly to the in guggul hypolipidemic In Indian the in lowering LDL cholesterol is R.K. S. M. N. of of in primary Google Scholar, S. trials with A Google Scholar), whereas the in is 18% P.O. Wolfe M.L. Bloedon L.T. Cucchiara A.J. DerMarderosian A.H. Cirigliano M.D. Rader D.J. Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial.JAMA. 2003; 290: 765-772Crossref PubMed Scopus (199) Google Scholar). The on the large in the rates to be In to a dosing in the trials, in metabolism likely to the M. A. C. of cytochrome P450 on and clinical Ther. 2007; PubMed Scopus Google Scholar). of the clinical trials reported the blood of P.O. Wolfe M.L. Bloedon L.T. Cucchiara A.J. DerMarderosian A.H. 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J.Y. farnesoid X receptor induction of bile salt export pump but X receptor to cholesterol Res. 2003; PubMed Scopus Google Scholar). the treatment with Z-guggulsterone and the was by findings that Z-guggulsterone through both and with higher of bile acids. In addition, Z-guggulsterone and induced BSEP the it to be whether and to which the to the hypolipidemic activity of In study that likely the hypolipidemic activity of guggul The CES1 induction and activity. CES1 induction the capacity of favors the synthesis of bile acids and elimination of cholesterol. induction of CES1 the capacity of likely increases the of this enzyme in the hydrolysis/reesterification VLDL The the metabolism of and the induction of Increased metabolism BSEP induction and decreases the induction of CES1. It that individuals with a higher capacity of metabolizing (probably induction of CES1 and have better hypolipidemic The the of the by for of bile salt export pump acid cytochrome P450 7A1 endoplasmic reticulum farnesoid X receptor X receptor