Expression of ABCG5 and ABCG8 Is Required for Regulation of Biliary Cholesterol Secretion

The major pathway for elimination of cholesterol in mammals is via secretion into bile. Biliary cholesterol secretion is mediated by the ATP-binding cassette (ABC) transporters ABCG5 (G5) and ABCG8 (G8) and is stimulated by cholesterol and by the non-cholesterol steroids cholate and diosgenin. To define the relationship between G5G8 expression and biliary cholesterol secretion, we measured G5 and G8 mRNA levels and biliary cholesterol concentrations in genetically manipulated mice expressing 0, 1, 2, 5, 10, or 16 copies of the two genes. Biliary cholesterol levels varied directly with G5G8 copy number and hepatic mRNA levels over a >16-fold range. Thus neither delivery of cholesterol to the transporter nor levels of cholesterol acceptors in bile were limiting under these conditions. In wild-type mice, cholate and diosgenin both increased biliary cholesterol concentrations 2–3-fold. The increase in biliary cholesterol content was dependent on expression of G5 and G8; neither steroid increased biliary cholesterol levels in G5G8–/– mice. Cholate treatment was associated with a farnesoid X receptor (FXR)-dependent increase in hepatic mRNA and protein levels of G5 and G8. In contrast to cholate, diosgenin treatment did not affect G5G8 expression. Diosgenin increased the expression of several pregnane X receptor (PXR) target genes and the choleretic effect of diosgenin was reduced by ∼70% in PXR knock-out mice. Thus G5 and G8 are required to modulate biliary cholesterol secretion in response to cholate and diosgenin, but the choleretic effects of these two steroids are mediated by different mechanisms requiring FXR and PXR, respectively. The major pathway for elimination of cholesterol in mammals is via secretion into bile. Biliary cholesterol secretion is mediated by the ATP-binding cassette (ABC) transporters ABCG5 (G5) and ABCG8 (G8) and is stimulated by cholesterol and by the non-cholesterol steroids cholate and diosgenin. To define the relationship between G5G8 expression and biliary cholesterol secretion, we measured G5 and G8 mRNA levels and biliary cholesterol concentrations in genetically manipulated mice expressing 0, 1, 2, 5, 10, or 16 copies of the two genes. Biliary cholesterol levels varied directly with G5G8 copy number and hepatic mRNA levels over a >16-fold range. Thus neither delivery of cholesterol to the transporter nor levels of cholesterol acceptors in bile were limiting under these conditions. In wild-type mice, cholate and diosgenin both increased biliary cholesterol concentrations 2–3-fold. The increase in biliary cholesterol content was dependent on expression of G5 and G8; neither steroid increased biliary cholesterol levels in G5G8–/– mice. Cholate treatment was associated with a farnesoid X receptor (FXR)-dependent increase in hepatic mRNA and protein levels of G5 and G8. In contrast to cholate, diosgenin treatment did not affect G5G8 expression. Diosgenin increased the expression of several pregnane X receptor (PXR) target genes and the choleretic effect of diosgenin was reduced by ∼70% in PXR knock-out mice. Thus G5 and G8 are required to modulate biliary cholesterol secretion in response to cholate and diosgenin, but the choleretic effects of these two steroids are mediated by different mechanisms requiring FXR and PXR, respectively. Cholesterol is an essential constituent of cell membranes that can be acquired by de novo synthesis from acetyl-CoA or obtained from the diet. Humans consuming Western diets synthesize ∼1 g of cholesterol/day and ingest ∼400 mg of cholesterol, of which ∼50% is absorbed (1Grundy S.M. Annu. Rev. Nutr. 1983; 3: 71-96Crossref PubMed Scopus (212) Google Scholar). An equivalent quantity of cholesterol is lost from the body via biliary secretion, either in the form of free cholesterol or after conversion to bile acids. Biliary cholesterol secretion is mediated by two ATP-binding cassette (ABC) 1The abbreviations used are: ABC, ATP-binding cassette; PXR, pregnane X receptor; FXR, farnesoid X receptor; CYP, cytochrome P450. transporters, ABCG5 (G5) and ABCG8 (G8), that function as a heterodimer at the apical membranes of hepatocytes (2Graf G.A. Yu L. Li W.P. Gerard R. Tuma P.L. Cohen J.C. Hobbs H.H. J. Biol. Chem. 2003; 278: 48275-48282Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar). Efficient biliary cholesterol secretion is essential for the maintenance of cholesterol homeostasis; humans and mice lacking G5 and G8 (G5G8–/–) have a marked reduction in biliary cholesterol secretion (3Miettinen T.A. Eur. J. Clin. Investig. 1980; 10: 27-35Crossref PubMed Scopus (203) Google Scholar, 4Yu L. Hammer R.E. Li-Hawkins J. Von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16237-16242Crossref PubMed Scopus (616) Google Scholar), and their hepatic and plasma levels of cholesterol are exquisitely sensitive to changes in dietary cholesterol content (4Yu L. Hammer R.E. Li-Hawkins J. Von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16237-16242Crossref PubMed Scopus (616) Google Scholar, 5Belamarich P.F. Deckelbaum R.J. Starc T.J. Dobrin B.E. Tint G.S. Salen G. Pediatrics. 1990; 86: 977-981PubMed Google Scholar). Whereas biliary cholesterol secretion is markedly reduced in G5G8–/– mice (that is, homozygous ABCG5 and ABCG8 double knock-out mice), transgenic mice overexpressing human G5 and G8 have increased biliary cholesterol concentrations and increased rates of fecal neutral sterol excretion (6Yu L. Li-Hawkins J. Hammer R.E. Berge K.E. Horton J.D. Cohen J.C. Hobbs H.H. J. Clin. Investig. 2002; 110: 671-680Crossref PubMed Scopus (622) Google Scholar). This finding indicated that an increase in G5G8 expression is sufficient to promote biliary cholesterol secretion. However, the relationship between G5G8 expression and biliary cholesterol secretion has not been systematically examined, and it is possible that other factors, such as biliary phospholipid levels (7Wittenburg H. Carey M.C. J. Clin. Investig. 2002; 110: 605-609Crossref PubMed Scopus (75) Google Scholar), limit the rate at which cholesterol is secreted into bile. Biliary cholesterol secretion is increased by cholesterol feeding. The increase in biliary cholesterol secretion induced by cholesterol feeding in mice is effected primarily through changes in the expression of the G5G8 transporter (8Berge K.E. Tian H. Graf G.A. Yu L. Grishin N.V. Schultz J. Kwiterovich P. Shan B. Barnes R. Hobbs H.H. Science. 2000; 290: 1771-1775Crossref PubMed Scopus (1386) Google Scholar). Cholesterol feeding activates the nuclear hormone receptor liver X receptor, which up-regulates the transcription of G5 and G8 (9Repa J.J. Berge K.E. Pomajzl C. Richardson J.A. Hobbs H. Mangelsdorf D.J. J. Biol. Chem. 2002; 277: 18793-18800Abstract Full Text Full Text PDF PubMed Scopus (702) Google Scholar). Treatment of wild-type mice with a liver X receptor agonist increased G5G8-mediated secretion of cholesterol into bile (10Yu L. York J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. J. Biol. Chem. 2003; 278: 15565-15570Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar). Conversely, liver X receptor knock-out mice fail to increase G5G8 expression in response to cholesterol feeding and, consequently, accumulate cholesterol in their livers (10Yu L. York J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. J. Biol. Chem. 2003; 278: 15565-15570Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar). Biliary cholesterol secretion is also increased by certain non-cholesterol steroids including cholate, a hydrophobic bile acid, and diosgenin (11Nervi F. Marinovic I. Rigotti A. Ulloa N. J. Clin. Investig. 1988; 82: 1818-1825Crossref PubMed Scopus (73) Google Scholar), a six-ring steroid found in yams. It is not known whether G5 and G8 mediate the choleretic effects of these non-cholesterol steroids. In mice, cholic acid feeding increases the mRNA levels of G5 and G8 in the liver (9Repa J.J. Berge K.E. Pomajzl C. Richardson J.A. Hobbs H. Mangelsdorf D.J. J. Biol. Chem. 2002; 277: 18793-18800Abstract Full Text Full Text PDF PubMed Scopus (702) Google Scholar), but whether this increase is required for the cholate-induced increase in biliary cholesterol secretion has not been determined. Diosgenin feeding increased biliary cholesterol secretion in mice without altering the mRNA levels of G5 and G8 in the liver (12Kosters A. Frijters R.J. Schaap F.G. Vink E. Plosch T. Ottenhoff R. Jirsa M. De Cuyper I.M. Kuipers F. Groen A.K. J. Hepatol. 2003; 38: 710-716Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar), suggesting a G5G8-independent pathway of biliary cholesterol secretion. To determine the role of G5 and G8 in regulating the amount of cholesterol secreted into bile, we examined the relationship between G5 and G8 expression and biliary cholesterol levels in genetically modified mice expressing 0, 1, 2, 5, 10, or 16 copies of the two genes. Next, we examined the role of G5 and G8 in modulating biliary cholesterol levels in response to cholate and diosgenin. Materials—Sodium cholate and diosgenin were purchased from Sigma-Aldrich. Sterols were obtained from either Steraloids Inc. (Newport, RI) or Sigma-Aldrich. Rabbit antibodies against the N-terminal regions of mouse ABCG5 (residues 2–375) and ABCG8 (2–400) were generated as described previously (4Yu L. Hammer R.E. Li-Hawkins J. Von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16237-16242Crossref PubMed Scopus (616) Google Scholar). Rabbit polyclonal antisera against calnexin and Grp78 (BIP) were from Stressgen Biotechnologies Corporation (Victoria, British Columbia, Canada). Animals and Diets—ABCG5/ABCG8 transgenic mice (G5G8Tg) were generated as described previously (6Yu L. Li-Hawkins J. Hammer R.E. Berge K.E. Horton J.D. Cohen J.C. Hobbs H.H. J. Clin. Investig. 2002; 110: 671-680Crossref PubMed Scopus (622) Google Scholar). Three lines of transgenic mice that expressed 3, 8, and 14 copies of the human G5G8 transgene (as determined by Southern blotting using human genomic DNA as a reference) were used in these experiments. Because each line of mice also has two wild-type G5 and G8 alleles, the mice expressed a total of 5, 10, and 16 copies of G5 and G8, respectively. Mice homozygous for a disrupted Abcg5 and Abcg8 (G5G8–/–) allele were generated as described previously (4Yu L. Hammer R.E. Li-Hawkins J. Von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16237-16242Crossref PubMed Scopus (616) Google Scholar). The G5G8–/– mice used in these studies were offspring of heterozygous mice of mixed genetic background (129S6SvEv and C57BL/6J). Mice lacking PXR (13Xie W. Barwick J.L. Downes M. Blumberg B. Simon C.M. Nelson M.C. Neuschwander-Tetri B.A. Brunt E.M. Guzelian P.S. Evans R.M. Nature. 2000; 406: 435-439Crossref PubMed Scopus (615) Google Scholar) were provided by Ronald Evans (Salk Institute, San Diego, CA). Mice lacking FXR (14Sinal C.J. Tohkin M. Miyata M. Ward J.M. Lambert G. Gonzalez F.J. Cell. 2000; 102: 731-744Abstract Full Text Full Text PDF PubMed Scopus (1495) Google Scholar) were provided by Frank Gonzalez (National Institutes of Health, Bethesda, MD). Mice were housed in plastic cages in a temperature-controlled room (22 °C) with a daylight cycle from 6 a.m. to 6 p.m. and were fed ad libitum a cereal-based rodent chow diet (Diet 7001, Harlan Teklad, Madison, WI) containing 0.02% cholesterol and 4% fat. All animal procedures were performed with the approval of the Institutional Animal Care and Research Advisory Committee at the University of Texas Southwestern Medical Center. Treatment of Mice with Cholate and Diosgenin—Diets containing 0.1% cholate, 0.2% cholate, or 1% diosgenin were made by mixing a powdered chow diet (Diet 7001, Harlan Teklad) with pure cholate or diosgenin. The diets were stored at 4 °C before use. Mice were housed individually 1 week before initiation of the diets and then were fed a diet containing either cholate or diosgenin or were fed with regular chow. Diets were dispensed from a feeder jar. Biliary Lipid Composition—Bile was collected from the gallbladder of anesthetized mice using a 30-gauge needle. The concentrations of cholesterol, bile acids, and phospholipids were measured as described previously (15Turley S.D. Daggy B.P. Dietschy J.M. Metabolism. 1991; 40: 1063-1073Abstract Full Text PDF PubMed Scopus (88) Google Scholar). Cannulation of the Common Bile Duct and Collection of Hepatic Bile—Mice were fasted overnight and then were anesthetized by intraperitoneal injection of 50 mg/kg pentobarbital (Nembutol). The gallbladder was removed, and the common bile duct was cannulated with a polyethylene-10 catheter. Hepatic bile was collected for 30 min, and bile flow (μl/min/100 g of body was determined a of 1 for bile B. Carey M.C. J. Lipid 38: Full Text PDF PubMed Google Scholar). Biliary bile S.D. Dietschy J.M. J. Lipid Full Text PDF PubMed Google Scholar), cholesterol H. P. H. I. J. Lipid 1980; Full Text PDF PubMed Google Scholar), and phospholipids M. S. T. I. Clin. PubMed Scopus Google Scholar) concentrations were determined of total of mg of liver or of the was by a in containing The was at g for at 4 The was collected and at g for at 4 The was in a containing 1% 50 8, and as protein concentrations of the membranes were determined using the were on and to The were with polyclonal antisera against mouse mouse calnexin and in with powdered and and then were with or and using was from using and was performed to the of as described previously J. J.L. Hammer R.E. Horton J.D. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, G. J. Horton J.D. Hammer R.E. J.L. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). The for PXR were and for and for and for and and for and of the are as the The between the were for using The relationship between transgene copy number and biliary cholesterol secretion rate was determined by Biliary Cholesterol to and of G5 and determine the relationship between G5G8 expression and biliary cholesterol secretion, we measured biliary cholesterol concentrations in genetically manipulated mice in which G5G8 expression varied over a range. was used to mice with either (G5G8–/–) or copy of G5 and G8, and transgenic lines were that a total of 5, 10, or 16 of the two genes. levels of ABCG5 and biliary cholesterol concentrations were to the number of copies of G5 and G8 in the To that the increased cholesterol content of gallbladder bile in the G5G8 transgenic increased biliary cholesterol secretion, biliary secretion rates were determined directly by the common bile Bile flow rates were in wild-type and in G5G8 transgenic mice The rate of biliary cholesterol secretion increased with expression of G5 and G8, biliary secretion of phospholipids and bile was not different in wild-type and transgenic over a of G5G8 the rate of biliary cholesterol secretion was determined by the expression of G5 and G8. the delivery of to the transporters nor the of sterol acceptors in the bile were over this of G5G8 secretion in transgenic mice. were in the common bile of wild-type mice and of mice expressing or 16 copies of the G5G8 and hepatic bile was collected for 30 Biliary cholesterol, bile acid, and phospholipid concentrations were determined and the secretion rate of each was determined from of bile the for each Cholate Biliary Cholesterol in feeding was associated with a increase in biliary cholesterol concentrations in wild-type mice The increase in biliary cholesterol in the wild-type was associated with a increase in the levels of G5 and G8 mRNA and protein 3, and Cholate feeding to increase biliary cholesterol secretion in G5G8–/– mice Cholate feeding an in the bile acid pathway known to be by bile acids. the of cholate to biliary cholesterol secretion was not to a to to cholate in these The effect of cholate on the expression of G5 and G8 was cholate feeding did not increase the levels of G5 and G8 mRNA or protein in the the other major of expression of these genes in mice Thus the increase in G5G8 expression in response to cholate is dependent on expressed in the liver that are not in the these are with the that of G5 and G8 expression is required for the in biliary cholesterol levels associated with cholate of cholate treatment on expression of ABCG5 and The from each mouse in was into two were from the and total were from the as described under containing of protein from each mouse in a were and was performed as described under was used as an containing of total from each mouse were and were by was used as an mRNA levels are expressed to the in wild-type mice, which was to The was and were Cholate Hepatic mRNA of G5 or G8 in acid the expression of several hepatic genes by the nuclear receptor To determine whether the effects of cholate on G5 and G8 are mediated by FXR, mice and their wild-type were with 0.2% cholate for Cholate treatment increased hepatic G5 and G8 mRNA levels by in wild-type mice but effect on G5 and G8 expression in mice Thus FXR is required for the of G5 and G8 induced by cholate feeding. Diosgenin Biliary Cholesterol in determine whether G5 and G8 mediate the increased biliary cholesterol secretion associated with diosgenin both G5G8–/– mice and their wild-type were fed diets containing 1% diosgenin for 1 has been previously K. H. K. N. J. Lipid Full Text PDF PubMed Google Scholar), diosgenin treatment was associated with a increase in biliary cholesterol levels in wild-type mice increase in G5 or G8 mRNA or protein levels was in either the livers and or the of wild-type which is with the of (12Kosters A. Frijters R.J. Schaap F.G. Vink E. Plosch T. Ottenhoff R. Jirsa M. De Cuyper I.M. Kuipers F. Groen A.K. J. Hepatol. 2003; 38: 710-716Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). ABCG5 and ABCG8 are as in the through the of the on both in a increase in their that the of and of the were not by diosgenin treatment In contrast to the wild-type mice, biliary cholesterol levels of the G5G8–/– mice did not with diosgenin G5 and G8 are required for the increase in biliary cholesterol but the effect is not to increased expression of G5 and G8 nor to a in the of G5 and G8 that the Diosgenin of PXR such as biliary secretion and hepatic expression by the nuclear receptor PXR L. J.L. T. J.M. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar) we examined the effect of diosgenin in mice. Diosgenin treatment increased the expression of a known PXR target in the liver and of the wild-type mice The effect of diosgenin on this was in mice (that is, homozygous PXR knock-out of a target of nuclear receptor receptor, was not by diosgenin indicated that diosgenin treatment to of of Biliary Cholesterol by Diosgenin by determine whether the increase in biliary cholesterol secretion associated with diosgenin treatment is mediated by PXR, biliary cholesterol levels were measured in mice after treatment with diosgenin for 1 The increase in biliary cholesterol levels was reduced by in the mice changes were in biliary levels of phospholipids or bile acids, the two other major biliary in wild-type or mice The mRNA levels of major biliary genes and Abcg8 were not by diosgenin treatment in wild-type mice are with a major role for the PXR pathway in the choleretic effect of diosgenin. The major of this were that the rate of biliary cholesterol secretion is directly to hepatic expression of G5 and G8 and that G5 and G8 are required for the choleretic effects of cholate and diosgenin. The of expression of G5 and G8 was the major of biliary cholesterol secretion rates over a of expression. the delivery of cholesterol to the transporter nor the levels of cholesterol acceptors in bile were of G5 and G8 was required for the of biliary cholesterol secretion by either cholate or diosgenin, but the two choleretic G5G8-mediated cholesterol secretion by different Cholate treatment was associated with a increase in hepatic G5 and G8 mRNA and which is with major effect at the In diosgenin did not increase expression levels of G5 and G8. major for the choleretic effect of diosgenin was mediated through The rate of cholesterol secretion into bile is from the of cholesterol in gallbladder bile (4Yu L. Hammer R.E. Li-Hawkins J. Von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. Proc. Natl. Acad. Sci. U. S. A. 2002; 99: 16237-16242Crossref PubMed Scopus (616) Google Scholar, L. Li-Hawkins J. Hammer R.E. Berge K.E. Horton J.D. Cohen J.C. Hobbs H.H. J. Clin. Investig. 2002; 110: 671-680Crossref PubMed Scopus (622) Google Scholar, L. York J. von Bergmann K. Lutjohann D. Cohen J.C. Hobbs H.H. J. Biol. Chem. 2003; 278: 15565-15570Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar, L. Von Bergmann K. Lutjohann D. Hobbs H.H. Cohen J.C. J. Lipid Full Text Full Text PDF PubMed Scopus Google Scholar). Because G5 and G8 are expressed in gallbladder A. R. 2003; PubMed Scopus Google Scholar), it is possible that the cholesterol in gallbladder bile of genetically manipulated mice the of cholesterol the gallbladder the biliary cholesterol secretion this of biliary cholesterol secretion rates in the G5G8 transgenic mice a relationship between the of G5G8 expression and the rate of biliary cholesterol secretion by K. A. Vink E. M. S. A.K. Yu H. J. R. N. R. Groen A.K. N. Salen G. PubMed Scopus Google Scholar) that the rate of biliary cholesterol secretion is markedly reduced in mice lacking G8 and that of to increase biliary cholesterol secretion in these cholate which increases G5G8 expression and biliary cholesterol increases biliary cholesterol secretion rates C.M. Ottenhoff R. C.M. Groen A.K. J. PubMed Scopus Google Scholar). injection of human G5 and G8 markedly increases cholesterol concentrations in gallbladder bile in G5G8–/– mice (2Graf G.A. Yu L. Li W.P. Gerard R. Tuma P.L. Cohen J.C. Hobbs H.H. J. Biol. Chem. 2003; 278: 48275-48282Abstract Full Text Full Text PDF PubMed Scopus (377) Google Scholar). In these G5 and G8 are expressed in the liver but not in the H. Hobbs and J. C. these that the increased cholesterol levels in gallbladder bile of mice an increase in biliary cholesterol secretion. previously that cholesterol feeding increases the expression of G5 and G8 (8Berge K.E. Tian H. Graf G.A. Yu L. Grishin N.V. Schultz J. Kwiterovich P. Shan B. Barnes R. Hobbs H.H. Science. 2000; 290: 1771-1775Crossref PubMed Scopus (1386) Google Scholar), in increased biliary cholesterol The of the that cholate also biliary cholesterol secretion by the expression of G5 and G8. Cholate feeding increases cholesterol in mice F. Cohen B. Carey M.C. J. PubMed Google Scholar), and the increased of dietary cholesterol promote biliary cholesterol secretion, but expression of G5 and G8 is required for this cholesterol and cholic acid, the major steroids in promote biliary cholesterol secretion by transcription of G5 and G8 in the Whereas cholesterol feeding increases the expression of G5 and G8 both in the liver and in the (8Berge K.E. Tian H. Graf G.A. Yu L. Grishin N.V. Schultz J. Kwiterovich P. Shan B. Barnes R. Hobbs H.H. Science. 2000; 290: 1771-1775Crossref PubMed Scopus (1386) Google Scholar), cholic acid has effect in the liver Cholate did not increase G5G8 expression in mice, that the effect of cholate on biliary cholesterol secretion is mediated by The known to increase biliary cholesterol secretion without G5G8 expression is diosgenin (12Kosters A. Frijters R.J. Schaap F.G. Vink E. Plosch T. Ottenhoff R. Jirsa M. De Cuyper I.M. Kuipers F. Groen A.K. J. Hepatol. 2003; 38: 710-716Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). The that diosgenin increases biliary cholesterol concentrations without the hepatic mRNA or protein levels of G5 or G8 (12Kosters A. Frijters R.J. Schaap F.G. Vink E. Plosch T. Ottenhoff R. Jirsa M. De Cuyper I.M. Kuipers F. Groen A.K. J. Hepatol. 2003; 38: 710-716Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, T. H. Hepatol. 2003; PubMed Scopus Google Scholar). However, G5 and G8 are required for the choleretic effect of increase in biliary cholesterol was in G5G8–/– mice. To the by which diosgenin stimulated biliary cholesterol secretion, we measured hepatic mRNA levels of several genes biliary transporters and nuclear receptor in mice. Diosgenin treatment was associated with increased hepatic mRNA levels of a target of the nuclear receptor PXR The finding that diosgenin increased expression of a PXR target with the that the PXR increased biliary cholesterol secretion in S.D. Dietschy J.M. Full Text PDF PubMed Scopus Google Scholar), that the increase in biliary cholesterol secretion be mediated by The increase in biliary cholesterol concentrations in mice was markedly in mice. a major of the effect of diosgenin on biliary cholesterol secretion was mediated by that diosgenin increases biliary cholesterol secretion by PXR, which in the expression of that promote cholesterol secretion in a by the of G5G8 that is on the or by the of the transporters in and are to the the to bile increases H. N. I.M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), but we have not been to of G5 or G8 G.A. Li Gerard I. A. Cohen J.C. Hobbs H.H. J. Clin. Investig. 2002; 110: PubMed Scopus Google Scholar). However, it possible that PXR increases the expression of that increase the of cholesterol the by the G5G8 by altering the of the or by the of cholesterol into the bile. studies be required to the mechanisms by which PXR secretion of cholesterol into bile. and for Ronald Evans and Frank for with and and for

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