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Bertrand Liagre - One of the best experts on this subject based on the ideXlab platform.
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Diosgenin induces death receptor 5 through activation of p38 pathway and promotes trail induced apoptosis in colon cancer cells
Cancer Letters, 2011Co-Authors: Clemence Lepage, David Yannick Leger, Julian Bertrand, Frederique Martin, Jeanlouis Beneytout, Bertrand LiagreAbstract:Previously, we demonstrated that Diosgenin induced apoptosis in colorectal cancer cell lines HCT-116 and HT-29. HT-29 cells have been reported to be one of the most resistant colorectal cancer cell lines to TRAIL-induced apoptosis. In this study, we investigated the effect of Diosgenin on TRAIL-induced apoptosis in HT-29 cells. We showed that Diosgenin sensitizes HT-29 cells to TRAIL-induced apoptosis. Mechanisms underlying this sensitization mainly involved Diosgenin-induced p38 MAPK pathway activation and subsequent DR5 overexpression. Furthermore, we showed that Diosgenin alone, TRAIL alone or combination treatment increased COX-2 expression and that the use of a COX-2 inhibitor further increased apoptosis induction.
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sedimentation field flow fractionation to study human erythroleukemia cell megakaryocytic differentiation after short period Diosgenin induction
Journal of Chromatography A, 2007Co-Authors: David Yannick Leger, Bertrand Liagre, Serge Battu, Philippe J P Cardot, Jeanlouis BeneytoutAbstract:Anti-cancer differentiation therapy could be one strategy to stop cancer cell proliferation. We propose a new sedimentation field flow fractionation (SdFFF) cell separation application in the field of cancer research. It concerns the study of megakaryocytic differentiation processes after a short exposure to an inducting agent (Diosgenin). Washout process and early dual SdFFF separation--removing the influence of Diosgenin and decreasing the influence of undifferentiated cells--resulted in the preparation of an enriched population to study the mechanism and kinetics of megakaryocytic differentiation. A short exposure to Diosgenin was able to induce complete differentiation leading to maximal maturation which ended naturally after 192h incubation without the influence of a secondary effect of Diosgenin. The study of isolated undifferentiated cells also showed that no resistance to Diosgenin was observed. This result suggested different sensitivities to differentiation induction, and SdFFF cell separation would be of great interest to explore this phenomena.
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Diosgenin induces cell cycle arrest and apoptosis in HEL cells with increase in intracellular calcium level, activation of cPLA2 and COX-2 overexpression.
International Journal of Oncology, 2004Co-Authors: David Leger, Cecile Corbiere, Bertrand Liagre, Jeanne Cook-moreau, Jeanlouis BeneytoutAbstract:Many natural components of plant extracts are studied for their beneficial effects for health and particularly on carcinogenesis chemoprevention. In the present study, we investigated the effects of Diosgenin on erythroleukemia HEL cells. Our results demonstrated that Diosgenin induced G2/M arrest of cell cycle progression through p21 up-regulation in a p53-independent pathway and strong induction of apoptosis in HEL cells. Apoptosis induction was accompanied by an increase in Bax/Bcl-2 ratio, PARP cleavage and DNA fragmentation. Moreover, we showed for the first time that Diosgenin provoked a collapse of mitochondrial membrane potential with an increase in intracellular calcium levels. It is well known that [Ca2+]i increase is one of the major activators of cytosolic PLA2. In our study, we demonstrated that Diosgenin treatment induced cPLA2 activation through translocation to the cellular membrane. Moreover, arachidonic acid metabolism activation led to cyclooxygenase-2 (COX-2) but not lipoxygenase overexpression. Surprisingly, we observed a COX-2 up-regulation associated with apoptosis induction by Diosgenin. These findings suggest that Diosgenin has a potential chemopreventive effect; future studies should evaluate the mechanism of COX-2 activation during Diosgenin-induced apoptosis in cancer cell lines.
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Diosgenin a plant steroid induces apoptosis in human rheumatoid arthritis synoviocytes with cyclooxygenase 2 overexpression
Arthritis Research & Therapy, 2004Co-Authors: Bertrand Liagre, Pascale Vergnesalle, Cecile Corbiere, Jean L Charissoux, Jean L BeneytoutAbstract:In the present study, we have shown for the first time that a plant steroid, Diosgenin, causes an inhibition of the growth of fibroblast-like synoviocytes from human rheumatoid arthritis, with apoptosis induction associated with cyclooxygenase-2 (COX-2) up-regulation. Celecoxib, a selective COX-2 inhibitor, provoked a large decrease in Diosgenin-induced apoptosis even in the presence of exogenous prostaglandin E2, whereas interleukin-1β, a COX-2 inducer, strongly increased Diosgenin-induced apoptosis of these synoviocytes. These findings suggest that the proapoptotic effect of Diosgenin is associated with overexpression of COX-2 correlated with overproduction of endogenous prostaglandin E2. We also observed a loss of mitochondrial membrane potential, caspase-3 activation, and DNA fragmentation after Diosgenin treatment.
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Induction of antiproliferative effect by Diosgenin through activation of p53, release of apoptosis-inducing factor (AIF) and modulation of caspase-3 activity in different human cancer cells
Cell Research, 2004Co-Authors: Cecile Corbiere, Bertrand Liagre, Faraj Terro, Jeanlouis BeneytoutAbstract:Previously, we demonstrated that a plant steroid, Diosgenin, altered cell cycle distribution and induced apoptosis in the human osteosarcoma 1547 cell line. The objective of this study was to investigate if the antiproliferative effect of Diosgenin was similar for different human cancer cell lines such as laryngocarcinoma HEp-2 and melanoma M4Beu cells. Moreover, this work essentially focused on the mitochondrial pathway. We found that Diosgenin had an important and similar antiproliferative effect on different types of cancer cells. In addition, our new results show that Diosgenin-induced apoptosis is caspase-3 dependent with a fall of mitochondrial membrane potential, nuclear localization of AIF and poly (ADP-ribose) polymerase cleavage. Diosgenin treatment also induces p53 activation and cell cycle arrest in the different cell lines studied.
Jeanlouis Beneytout - One of the best experts on this subject based on the ideXlab platform.
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Diosgenin induces death receptor 5 through activation of p38 pathway and promotes trail induced apoptosis in colon cancer cells
Cancer Letters, 2011Co-Authors: Clemence Lepage, David Yannick Leger, Julian Bertrand, Frederique Martin, Jeanlouis Beneytout, Bertrand LiagreAbstract:Previously, we demonstrated that Diosgenin induced apoptosis in colorectal cancer cell lines HCT-116 and HT-29. HT-29 cells have been reported to be one of the most resistant colorectal cancer cell lines to TRAIL-induced apoptosis. In this study, we investigated the effect of Diosgenin on TRAIL-induced apoptosis in HT-29 cells. We showed that Diosgenin sensitizes HT-29 cells to TRAIL-induced apoptosis. Mechanisms underlying this sensitization mainly involved Diosgenin-induced p38 MAPK pathway activation and subsequent DR5 overexpression. Furthermore, we showed that Diosgenin alone, TRAIL alone or combination treatment increased COX-2 expression and that the use of a COX-2 inhibitor further increased apoptosis induction.
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sedimentation field flow fractionation to study human erythroleukemia cell megakaryocytic differentiation after short period Diosgenin induction
Journal of Chromatography A, 2007Co-Authors: David Yannick Leger, Bertrand Liagre, Serge Battu, Philippe J P Cardot, Jeanlouis BeneytoutAbstract:Anti-cancer differentiation therapy could be one strategy to stop cancer cell proliferation. We propose a new sedimentation field flow fractionation (SdFFF) cell separation application in the field of cancer research. It concerns the study of megakaryocytic differentiation processes after a short exposure to an inducting agent (Diosgenin). Washout process and early dual SdFFF separation--removing the influence of Diosgenin and decreasing the influence of undifferentiated cells--resulted in the preparation of an enriched population to study the mechanism and kinetics of megakaryocytic differentiation. A short exposure to Diosgenin was able to induce complete differentiation leading to maximal maturation which ended naturally after 192h incubation without the influence of a secondary effect of Diosgenin. The study of isolated undifferentiated cells also showed that no resistance to Diosgenin was observed. This result suggested different sensitivities to differentiation induction, and SdFFF cell separation would be of great interest to explore this phenomena.
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Diosgenin induces cell cycle arrest and apoptosis in HEL cells with increase in intracellular calcium level, activation of cPLA2 and COX-2 overexpression.
International Journal of Oncology, 2004Co-Authors: David Leger, Cecile Corbiere, Bertrand Liagre, Jeanne Cook-moreau, Jeanlouis BeneytoutAbstract:Many natural components of plant extracts are studied for their beneficial effects for health and particularly on carcinogenesis chemoprevention. In the present study, we investigated the effects of Diosgenin on erythroleukemia HEL cells. Our results demonstrated that Diosgenin induced G2/M arrest of cell cycle progression through p21 up-regulation in a p53-independent pathway and strong induction of apoptosis in HEL cells. Apoptosis induction was accompanied by an increase in Bax/Bcl-2 ratio, PARP cleavage and DNA fragmentation. Moreover, we showed for the first time that Diosgenin provoked a collapse of mitochondrial membrane potential with an increase in intracellular calcium levels. It is well known that [Ca2+]i increase is one of the major activators of cytosolic PLA2. In our study, we demonstrated that Diosgenin treatment induced cPLA2 activation through translocation to the cellular membrane. Moreover, arachidonic acid metabolism activation led to cyclooxygenase-2 (COX-2) but not lipoxygenase overexpression. Surprisingly, we observed a COX-2 up-regulation associated with apoptosis induction by Diosgenin. These findings suggest that Diosgenin has a potential chemopreventive effect; future studies should evaluate the mechanism of COX-2 activation during Diosgenin-induced apoptosis in cancer cell lines.
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Induction of antiproliferative effect by Diosgenin through activation of p53, release of apoptosis-inducing factor (AIF) and modulation of caspase-3 activity in different human cancer cells
Cell Research, 2004Co-Authors: Cecile Corbiere, Bertrand Liagre, Faraj Terro, Jeanlouis BeneytoutAbstract:Previously, we demonstrated that a plant steroid, Diosgenin, altered cell cycle distribution and induced apoptosis in the human osteosarcoma 1547 cell line. The objective of this study was to investigate if the antiproliferative effect of Diosgenin was similar for different human cancer cell lines such as laryngocarcinoma HEp-2 and melanoma M4Beu cells. Moreover, this work essentially focused on the mitochondrial pathway. We found that Diosgenin had an important and similar antiproliferative effect on different types of cancer cells. In addition, our new results show that Diosgenin-induced apoptosis is caspase-3 dependent with a fall of mitochondrial membrane potential, nuclear localization of AIF and poly (ADP-ribose) polymerase cleavage. Diosgenin treatment also induces p53 activation and cell cycle arrest in the different cell lines studied.
Jayadev Raju - One of the best experts on this subject based on the ideXlab platform.
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Diosgenin a steroid saponin constituent of yams and fenugreek emerging evidence for applications in medicine
2012Co-Authors: Jayadev Raju, Chinthalapally V RaoAbstract:Phytochemicals found in foods and spices are progressively gaining popularity over conventional synthetic drugs mainly because they act via multiple molecular targets that synergize to efficiently prevent or treat chronic illnesses. Phytochemicals are also safe (with minimal or no toxic or side effects) with better bioavailability. Food saponins have been used in complimentary and traditional medicine against a variety of diseases including several cancers. Diosgenin, a naturally-occurring steroid saponin is found abundantly in legumes (Trigonella sp.) and yams (Dioscorea sp.). Diosgenin is a precursor of various synthetic steroidal drugs that are extensively used in the pharmaceutical industry. Over the past two decades, a series of pre-clinical and mechanistic studies have been independently conducted to understand the beneficial role of Diosgenin against metabolic diseases (hypercholesterolemia, dyslipidemia, diabetes and obesity), inflammation and cancer. In experimental models of obesity, Diosgenin decreases plasma and hepatic triglycerides and improves glucose homeostasis plausibly by promoting adipocyte differentiation and inhibiting inflammation in adipose tissues. A limited number of experiments have been conducted to understand the preclinical efficacy of Diosgenin as a chemopreventive/therapeutic agent against cancers of several organ sites. Mechanistic studies using in vitro models suggest that Diosgenin suppresses cancer cell growth through multiple cell signaling events associated with proliferation, differentiation, apoptosis, inflammation and oncogenesis. This chapter provides a comprehensive review of the biological activity of Diosgenin that contributes to several diseases in its role as a health beneficial phytochemical by citing new studies. In addition, Diosgenin’s safety with regards to its potential toxicity is also critically discussed. Altogether, the findings from pre-clinical and mechanistic studies strongly implicate the use of Diosgenin as a novel multi-target based chemopreventive or therapeutic agent against several chronic diseases.
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cancer chemopreventive and therapeutic effects of Diosgenin a food saponin
Nutrition and Cancer, 2009Co-Authors: Jayadev Raju, Rekha MehtaAbstract:Cancer chemoprevention is a strategy taken to retard, regress, or resist the multistep process of carcinogenesis, including the blockage of its vital morphogenetic milestones viz. normal-preneoplasia-neoplasia-metastasis. For several reasons, including safety, minimal (or no) toxicity and side-effects, and better availability, alternatives such as naturally occurring phytochemicals that are found in foods are becoming increasingly popular over synthetic drugs. Food saponins have been used in complimentary and traditional medicine against a variety of diseases including several cancers. Diosgenin, a naturally occurring steroid saponin found abundantly in legumes and yams, is a well-known precursor of various synthetic steroidal drugs that are extensively used in the pharmaceutical industry. Over the past decade, a series of preclinical and mechanistic studies have been conducted to understand the role of Diosgenin as a chemopreventive/therapeutic agent against several cancers. This review highlights the biological activity of Diosgenin that contributes to cancer chemoprevention and control. The anticancer mode of action of Diosgenin has been demonstrated via modulation of multiple cell signaling events involving critical molecular candidates associated with growth, differentiation, apoptosis, and oncogenesis. Altogether, these preclinical and mechanistic findings strongly implicate the use of Diosgenin as a novel, multitarget-based chemopreventive or therapeutic agent against several cancer types. Future research in this field will help to establish not only whether Diosgenin is safe and efficacious as a chemopreventive agent against several human cancers, but also to develop and evaluate standards of evidence for health claims for Diosgenin-containing foods as they become increasingly popular and enter the marketplace labeled as functional foods and nutraceuticals.
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Diosgenin a naturally occurring furostanol saponin suppresses 3 hydroxy 3 methylglutaryl coa reductase expression and induces apoptosis in hct 116 human colon carcinoma cells
Cancer Letters, 2007Co-Authors: Jayadev Raju, Ranjana P BirdAbstract:A growing body of experimental evidence suggests the therapeutic potential of Diosgenin, a steroid [corrected] saponin against several cancers. However, precise molecular and cellular mechanisms underlying the modes of action of this compound against colon cancer remain only partially understood. In this study, we investigated if the anticancer mechanism of Diosgenin in HCT-116 human colon carcinoma cells involves modulation in the expression of 3-hydroxy-3-methylglutaryl Co-enzyme A (HMG-CoA) reductase, the rate-limiting enzyme of the cholesterol biosynthetic pathway. Diosgenin treatment resulted in a dose-dependent decrease in the viability and growth of HCT-116 cells. The IC(50) cytotoxic dose of Diosgenin in HCT-116 was approximately 35 microM after 24h, while concentrations of approximately 32 microM or greater decreased the percent viable cells by 50%. Higher doses of Diosgenin (30-40 microM) effectively inhibited recovery of cells for up to 24h post-treatments. At sub-cytotoxic doses, Diosgenin induced a dose-dependent increase in apoptotic demise. In part, the apoptotic mechanism was through the cleavage of the 116 kDa poly (ADP-ribose) polymerase protein to the 85kDa fragment. The expression of HMG-CoA reductase at both mRNA and protein levels was significantly lowered by increasing concentrations of Diosgenin. This was accompanied by a concomitant dose-dependent decrease in the expression of p21 ras and beta-catenin. In conclusion, our data demonstrates that the food saponin, Diosgenin is a potent inhibitor of HCT-116 human colon carcinoma cells by growth inhibition and induction of apoptosis. Importantly, our result identifies that the growth suppressive or apoptotic activity of Diosgenin may involve cholesterol homeostasis.
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Diosgenin a steroid saponin of trigonella foenum graecum fenugreek inhibits azoxymethane induced aberrant crypt foci formation in f344 rats and induces apoptosis in ht 29 human colon cancer cells
Cancer Epidemiology Biomarkers & Prevention, 2004Co-Authors: Jayadev Raju, Jagan M R Patlolla, Malisetty V Swamy, Chinthalapally V RaoAbstract:Trigonella foenum graecum (fenugreek) is traditionally used to treat disorders such as diabetes, high cholesterol, wounds, inflammation, and gastrointestinal ailments. Recent studies suggest that fenugreek and its active constituents may possess anticarcinogenic potential. We evaluated the preventive efficacy of dietary fenugreek seed and its major steroidal saponin constituent, Diosgenin, on azoxymethane-induced rat colon carcinogenesis during initiation and promotion stages. Preneoplastic colonic lesions or aberrant crypt foci (ACF) were chosen as end points. In addition, we assessed the mechanism of tumor growth inhibition of Diosgenin in HT-29 human colon cancer cells. To evaluate the effect of the test agent during the initiation and postinitiation stages, 7-week-old male F344 rats were fed experimental diets containing 0% or 1% fenugreek seed powder (FSP) or 0.05% or 0.1% Diosgenin for 1 week and were injected with azoxymethane (15 mg/kg body weight). Effects during the promotional stage were studied by feeding 1% FSP or 0.1% Diosgenin 4 weeks after the azoxymethane injections. Rats were sacrificed 8 weeks after azoxymethane injection, and their colons were evaluated for ACF. We found that, by comparison with control, continuous feeding of 1% FSP and 0.05% and 0.1% Diosgenin suppressed total colonic ACF up to 32%, 24%, and 42%, respectively (P < or = 0.001 to 0.0001). Dietary FSP at 1% and Diosgenin at 0.1% fed only during the promotional stage also inhibited total ACF up to 33% (P < or = 0.001) and 39% (P < or = 0.0001), respectively. Importantly, continuous feeding of 1% FSP or 0.05% or 0.1% Diosgenin reduced the number of multicrypt foci by 38%, 20%, and 36% by comparison with the control assay (P < or = 0.001). In addition, 1% FSP or 0.1% Diosgenin fed during the promotional stage caused a significant reduction (P < or = 0.001) of multicrypt foci compared with control. Dietary Diosgenin at 0.1% and 0.05% inhibited total colonic ACF and multicrypt foci formation in a dose-dependent manner. Results from the in vitro experiments indicated that Diosgenin inhibits cell growth and induces apoptosis in the HT-29 human colon cancer cell line in a dose-dependent manner. Furthermore, Diosgenin induced apoptosis in HT-29 cells at least in part by inhibition of bcl-2 and by induction of caspase-3 protein expression. On the basis of these findings, the fenugreek constituent Diosgenin seems to have potential as a novel colon cancer preventive agent.
Gautam Sethi - One of the best experts on this subject based on the ideXlab platform.
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pro apoptotic and anti cancer properties of Diosgenin a comprehensive and critical review
Nutrients, 2018Co-Authors: Gautam Sethi, Muthu K Shanmugam, Sudha Warrier, Myriam Merarchi, Frank Arfuso, Alan Prem Kumar, Anupam BishayeeAbstract:Novel and alternative options are being adopted to combat the initiation and progression of human cancers. One of the approaches is the use of molecules isolated from traditional medicinal herbs, edible dietary plants and seeds that play a pivotal role in the prevention/treatment of cancer, either alone or in combination with existing chemotherapeutic agents. Compounds that modulate these oncogenic processes are potential candidates for cancer therapy and may eventually make it to clinical applications. Diosgenin is a naturally occurring steroidal sapogenin and is one of the major bioactive compounds found in dietary fenugreek (Trigonella foenum-graecum) seeds. In addition to being a lactation aid, Diosgenin has been shown to be hypocholesterolemic, gastro- and hepato-protective, anti-oxidant, anti-inflammatory, anti-diabetic, and anti-cancer. Diosgenin has a unique structural similarity to estrogen. Several preclinical studies have reported on the pro-apoptotic and anti-cancer properties of Diosgenin against a variety of cancers, both in in vitro and in vivo. Diosgenin has also been reported to reverse multi-drug resistance in cancer cells and sensitize cancer cells to standard chemotherapy. Remarkably, Diosgenin has also been reported to be used by pharmaceutical companies to synthesize steroidal drugs. Several novel Diosgenin analogs and nano-formulations have been synthesized with improved anti-cancer efficacy and pharmacokinetic profile. In this review we discuss in detail the multifaceted anti-cancer properties of Diosgenin that have found application in pharmaceutical, functional food, and cosmetic industries; and the various intracellular molecular targets modulated by Diosgenin that abrogate the oncogenic process.
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Diosgenin a steroidal saponin inhibits stat3 signaling pathway leading to suppression of proliferation and chemosensitization of human hepatocellular carcinoma cells
Cancer Letters, 2010Co-Authors: Prasana Priscilla Fernandez, Peramaiyan Rajendran, Kam M Hui, Gautam SethiAbstract:Constitutive activation of STAT3 has been shown in several human cancers and transformed cell lines including hepatocellular carcinoma (HCC). In the present report, we investigated whether Diosgenin, a steroidal saponin isolated from fenugreek can modulate the STAT3 signaling pathway. We found that Diosgenin inhibited both constitutive and inducible activation of STAT3 with no effect on STAT5. The activation of c-Src, JAK1 and JAK2 implicated in STAT3 activation, were also suppressed by this saponin. Pervanadate reversed the Diosgenin-induced downregulation of STAT3, suggesting the involvement of a protein tyrosine phosphatase. Indeed, we found that Diosgenin can induce the expression of Src homology 2 phosphatase 2 (SH-PTP2) that correlated with downregulation of constitutive STAT3 activation. Diosgenin also downregulated the expression of various STAT3-regulated gene products, inhibited proliferation and potentiated the apoptotic effects of paclitaxel and doxorubicin. Overall, these results suggest that Diosgenin is a novel blocker of the STAT3 activation pathway, with a potential role in the treatment of HCC and other cancers.
Liqing Yu - One of the best experts on this subject based on the ideXlab platform.
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Diosgenin stimulation of fecal cholesterol excretion in mice is not npc1l1 dependent
Journal of Lipid Research, 2009Co-Authors: Ryan E Temel, Jonathan Mark Brown, Yiannis A. Ioannou, Joanna P Davies, Weiqing Tang, Liqing YuAbstract:Diosgenin exists in some food supplements and herbal medicines and lowers plasma cholesterol by increasing fecal cholesterol excretion. It is believed that Diosgenin promotes fecal cholesterol excretion by stimulating biliary cholesterol secretion and decreasing intestinal cholesterol absorption. Niemann-Pick C1-like 1 (NPC1L1) was recently identified as an essential protein for intestinal cholesterol absorption. To determine the relative contribution of biliary secretion and intestinal absorption of cholesterol in Diosgenin-stimulated fecal cholesterol excretion, wild-type (WT) and NPC1L1-knockout (L1KO) mice were fed a diet with or without 1% Diosgenin. Fecal cholesterol excretion (μmol/day/100 g body weight) increased in Diosgenin-fed WT and L1KO mice from 4.2 to 52 and from 63 to 140, respectively. Surprisingly, this increase in Diosgenin-treated versus untreated L1KO mice (77) was even greater than that seen in Diosgenin-treated versus untreated WT mice (47.8). Additionally, WT and L1KO mice fed the Diosgenin diet had similar increases in biliary cholesterol concentration, despite unaltered hepatic expression of the hepatobiliary cholesterol transporter, ATP binding cassette transporters G5 and G8. Facilitated cholesterol excretion in Diosgenin-treated WT and L1KO mice was associated with decreased hepatic and plasma cholesterol and increased liver expression of cholesterol synthetic genes. In contrast, Diosgenin had no effect on the intestinal expression of NPC1L1 and cholesterol synthetic genes. In an in vitro assay, Diosgenin was unable to block NPC1L1-dependent cholesterol uptake. In conclusion, Diosgenin stimulation of fecal cholesterol excretion is independent of NPC1L1-mediated cholesterol absorption.
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Expression of ABCG5 and ABCG8 is required for regulation of biliary cholesterol secretion
Journal of Biological Chemistry, 2005Co-Authors: Liqing Yu, Amy D.b. Liverman, Joyce J. Repa, Sarita Gupta, Antonio Moschetta, Helen H Hobbs, Fang Xu, Jonathan C CohenAbstract: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 approximately 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.