Progress 10/01/12 to 01/03/17
Outputs
Target Audience:Several publications have been produced including poster presentation abstracts at national meetings to the scientific community. In addition manuscripts have been published in scientifc journals targeted at the national and international scientific community Two University of Nevada Coperative Extension (UNCE) Special Publication factsheets have been submitted for peer review with the intention of translating the research from the lab in order to provide the information to public helath related professionals to facilitate provision of the information to the lay community. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?This project has trained one PhD student and 3 MS students and provided opportunities for undergraduate students to gain practical experience in molecular biology techniques and the field of molecular nutrition How have the results been disseminated to communities of interest?The data resulting from these studies has been published in Scientiifc journals, presented at national/international scientific meetings and has been submitted through UNCE as special publication facts sheets to facilitate provision of the findings to healthcare professionals and the lay community. What do you plan to do during the next reporting period to accomplish the goals?
Nothing Reported
Impacts
What was accomplished under these goals?
Using rodent models we have identified that GSPE exerts effects on intestinal bile acid transporters as a new mechanism leading to the in vivo triglyceride-lowering effects of this natural product. Down-regulation of FXR-dependent bile acid transporter expression leads to a decrease in the reabsorption of bile acids in the distal portion of the small intestine; thisleads to increased excretion of bile acids in the feces and reduced levels of bile acids returning to the liver. Reduced bile acid recirculation to the liver induces triglyceride (TG) catablism via increased beta-oxidation, and the subsequent use of the TG breakdown products to increase cholesterol synthesis; this newly made cholesterol is subsequentyly used to make bile acids, to replace those lost via the feces. This was an important finding indicating the importance of the gut-liver axis in the molecular actions of GSPE. These findings were published as follows: Dietary procyanidins selectively modulate intestinal farnesoid X receptor-regulated gene expression to alter enterohepatic bile acid recirculation: elucidation of a novel mechanism to reduce triglyceridemia. Heidker RM, Caiozzi GC, Ricketts ML. Mol Nutr Food Res. 2016 Apr;60(4):727-36. doi: 10.1002/mnfr.201500795. PMID: 26718753 We have also discovered that GSPE acts as an HDAC inhibitor and in so doing increases the ability of the nuclear receptor peroxisome proliferator activator receptor alpha (PPAR alpha) to increase target gene expression, thereby leading to increased beta-oxidation,ultimatleycontributing to reduced triglyceride levels following GSPE administration. These finsings were published as follows: A grape seed procyanidin extract inhibits HDAC activity leading to increased Pparα phosphorylation and target-gene expression. Downing LE, Ferguson BS, Rodriguez K, Ricketts ML. Mol Nutr Food Res. 2016 Sep 14. doi: 10.1002/mnfr.201600347. [Epub ahead of print] PMID: 27624175 (This manuscript is scheduled to be featured on the front cover of the February 2017 issue of the journal) We also determined that GSPE provides additive and complementary efficacy as a lipid-lowering combination therapy with the bile acid sequestrant cholestyramine in vivo in a rodent model by attenuating hepatic cholesterol synethsis, enhancing bile acid biosynthesis and decreaseing lipogensis. These findings were published as follows: Grape Seed Procyanidins and Cholestyramine Differentially Alter Bile Acid and Cholesterol Homeostatic Gene Expression in Mouse Intestine and Liver. Heidker RM, Caiozzi GC, Ricketts ML. PLoS One. 2016 Apr 25;11(4):e0154305. doi: 10.1371/journal.pone.0154305. PMID: 27111442 We have fractionated GSPE to determine the component within the extract that exerts the co-agonisitic effects with respect to bile acid bound FXR. We have isolated 25 fractions and performed transient transfection studies to determine their ability to enhance bile acid bound FXR transactivation and characterized the positive fraction by mass spec analysis. We have determined that a dimer and a dimer gallate are important for the FXR co-agonistic effects of GSPE. This reserach has been submitted to Experimental Biology 2017 and a manuscript is currently in preparation. The following special publication fact sheets have been submitted through UNCE for peer review in order to provide healthcare professionals with the information reltaing to these lab-based studies: Grape Seed Procyanidin Extract (GSPE): Findings from Lab-based Research and Implications for Improving Human Health and Nutrition" Marie-Louise Ricketts, Laura Downing and Loretta Singletary Potential Beneficial Health effects of a Grape Seed Procyanidin Extract (GSPE): Results from a mouse model MarieLouise Ricketts and Loretta Singletary
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2016
Citation:
Grape Seed Procyanidins and Cholestyramine Differentially Alter Bile Acid and Cholesterol Homeostatic Gene Expression
in Mouse Intestine and Liver.
Heidker RM, Caiozzi GC, Ricketts ML.
PLoS One. 2016 Apr 25;11(4):e0154305. doi: 10.1371/journal.pone.0154305.
PMID: 27111442
- Type:
Journal Articles
Status:
Published
Year Published:
2016
Citation:
Mechanistic insight into nuclear receptor-mediated regulation of bile acid metabolism and lipid homeostasis by grape seed
procyanidin extract (GSPE)
Cell Biochemistry and Function
Laura E. Downing, Daniel Edgar, Patricia A. Ellison and Marie-Louise Ricketts
- Type:
Conference Papers and Presentations
Status:
Submitted
Year Published:
2017
Citation:
Determination of the Bioactive Components in a Grape Seed Procyanidin Extract Responsible for Enhanced Farnesoid X
Receptor Transactivation
Kelvin Rodriguez and Marie-Louise Ricketts, Ph.D.
- Type:
Other
Status:
Under Review
Year Published:
2017
Citation:
Grape Seed Procyanidin Extract (GSPE): Findings from Lab-based Research and Implications for Improving Human
Health and Nutrition
Marie-Louise Ricketts, Laura Downing and Loretta Singletary
UNCE Special Publication Fact sheet
- Type:
Other
Status:
Under Review
Year Published:
2017
Citation:
Potential Beneficial Health effects of a Grape Seed Procyanidin Extract (GSPE): Results from a mouse model
Marie-Louise Ricketts and Loretta Singletary
UNCE Special Publication Fact Sheet
|
Progress 10/01/16 to 01/03/17
Outputs
Target Audience:Project ended 6/30/2015 Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?
Nothing Reported
How have the results been disseminated to communities of interest?
Nothing Reported
What do you plan to do during the next reporting period to accomplish the goals?
Nothing Reported
Impacts
What was accomplished under these goals?
Project ended 6/30/2015
Publications
|
Progress 10/01/15 to 09/30/16
Outputs
Target Audience:Several publications have been produced including poster presentation abstracts at national meetings to the scientific community. In addition manuscripts have been published in scientifc journals targeted at the national and international scientific community Two University of Nevada Coperative Extension (UNCE) Special Publication factsheets have been submitted for peer review with the intention of translating the research from the lab in order to provide the information to public helath related professionals to facilitate provision of the information to the lay community Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?This project has trained one PhD student and 3 MS students and provided opportunities for undergraduate students to gain practical experience in molecular biology techniques and the field of molecular nutrition How have the results been disseminated to communities of interest?The data resulting from these studies has been published in Scientiifc journals, presented at national/international scientific meetings and has been submitted through UNCE as special publication facts sheets to facilitate provision of the findings to healthcare professionals and the lay community What do you plan to do during the next reporting period to accomplish the goals?Funding for this project has now ended
Impacts
What was accomplished under these goals?
Using rodent models we have identified that GSPE exerts effects on intestinal bile acid transporters asa new mechanism leading to the in vivo triglyceride-lowering effects of this natural product. Down-regulation of FXR-dependent bile acid transporter expression leads to a decrease in the reabsorption of bile acids in the distal portion of the small intestine; this leads to increased excretion of bile acids in the feces and reduced levels of bile acids returning to the liver. Reduced bile acid recirculation to the liver induces triglyceride (TG) catablism via increased beta-oxidation, and the subsequent use of the TG breakdown products to increase cholesterol synthesis; this newly made cholesterolis subsequentyly used to make bile acids, to replace those lost via the feces. This was an important finding indicating the importance of the gut-liver axis in the molecular actions of GSPE. These findings were published as follows: Dietary procyanidins selectively modulate intestinal farnesoid X receptor-regulated gene expression to alter enterohepatic bile acid recirculation: elucidation of a novel mechanism to reduce triglyceridemia.Heidker RM, Caiozzi GC,Ricketts ML.Mol Nutr Food Res. 2016 Apr;60(4):727-36. doi: 10.1002/mnfr.201500795. PMID: 26718753 We have also discovered that GSPE acts as an HDAC inhibitor and in so doing increases the ability of the nuclear receptor peroxisome proliferator activator receptor alpha (PPAR alpha) to increase target gene expression, thereby leading to increased beta-oxidation,ultimatleycontributing to reduced triglyceride levels following GSPE administration. These finsings were published as follows:A grape seed procyanidin extract inhibits HDAC activity leading to increased Pparα phosphorylation and target-gene expression.Downing LE, Ferguson BS, Rodriguez K,Ricketts ML.Mol Nutr Food Res. 2016 Sep 14. doi: 10.1002/mnfr.201600347. [Epub ahead of print] PMID: 27624175 (This manuscript is scheduled to be featured on the front cover of the February 2017 issue of the journal) We also determined that GSPE provides additive and complementary efficacy as a lipid-lowering combination therapy with the bile acid sequestrant cholestyramine in vivo in a rodent model by attenuating hepatic cholesterol synethsis, enhancing bileacid biosynthesis and decreaseing lipogensis. These findings were published as follows:Grape Seed Procyanidins and Cholestyramine Differentially Alter Bile Acid and Cholesterol Homeostatic Gene Expression in Mouse Intestine and Liver.Heidker RM, Caiozzi GC,Ricketts ML.PLoS One. 2016 Apr 25;11(4):e0154305. doi: 10.1371/journal.pone.0154305. PMID: 27111442 We have fractionated GSPE to determine the component within the extract that exerts the co-agonisitic effects with respect to bile acid bound FXR. We have isolated 25 fractions and performed transient transfection studies to determine their ability to enhance bile acid bound FXR transactivation and characterized the positive fraction by mass spec analysis. We have determined that a dimer and a dimer gallate are important for the FXR co-agonistic effects of GSPE. This reserach has been submitted to Experimental Biology 2017 and a manuscript is currently in preparation. The following special publication fact sheets have been submitted through UNCE for peer review in order to provide healthcare professionals with the information reltaing to these lab-based studies: Grape Seed Procyanidin Extract (GSPE): Findings from Lab-based Research and Implications for Improving Human Health and Nutrition"Marie-Louise Ricketts, Laura Downing and Loretta Singletary Potential Beneficial Health effects of a Grape Seed Procyanidin Extract (GSPE): Results from a mouse modelMarie-Louise Ricketts and Loretta Singletary
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2016
Citation:
Grape Seed Procyanidins and Cholestyramine Differentially Alter Bile Acid and Cholesterol Homeostatic Gene Expression in Mouse Intestine and Liver.
Heidker RM, Caiozzi GC, Ricketts ML.
PLoS One. 2016 Apr 25;11(4):e0154305. doi: 10.1371/journal.pone.0154305.
PMID: 27111442
- Type:
Journal Articles
Status:
Published
Year Published:
2016
Citation:
A grape seed procyanidin extract inhibits HDAC activity leading to increased Ppar? phosphorylation and target-gene expression.
Downing LE, Ferguson BS, Rodriguez K, Ricketts ML.
Mol Nutr Food Res. 2016 Sep 14. doi: 10.1002/mnfr.201600347. [Epub ahead of print]
PMID: 27624175
- Type:
Journal Articles
Status:
Accepted
Year Published:
2017
Citation:
Mechanistic insight into nuclear receptor-mediated regulation of bile acid metabolism and lipid homeostasis by grape seed procyanidin extract (GSPE)
Cell Biochemistry and Function
Laura E. Downing, Daniel Edgar, Patricia A. Ellison and Marie-Louise Ricketts
- Type:
Conference Papers and Presentations
Status:
Submitted
Year Published:
2017
Citation:
Determination of the Bioactive Components in a Grape Seed Procyanidin Extract Responsible for Enhanced Farnesoid X Receptor Transactivation
Kelvin Rodriguez and Marie-Louise Ricketts, Ph.D.
- Type:
Other
Status:
Under Review
Year Published:
2017
Citation:
Grape Seed Procyanidin Extract (GSPE): Findings from Lab-based Research and Implications for Improving Human Health and Nutrition
Marie-Louise Ricketts, Laura Downing and Loretta Singletary
UNCE Special Publication Fact sheet
- Type:
Other
Status:
Under Review
Year Published:
2017
Citation:
Potential Beneficial Health effects of a Grape Seed Procyanidin Extract (GSPE): Results from a mouse model
Marie-Louise Ricketts and Loretta Singletary
UNCE Special Publication Fact Sheet
|
Progress 10/01/14 to 09/30/15
Outputs
Target Audience:During the current reporting period the results of the research conducted were presented at a national conference to members of the scientific community. Both National and International researchers attended the Experimental Biology conference in 2015, which was held in Boston, MA. In addition, the research was also presented in poster format to the local Reno/Sparks lay community at the College of Agriculture, Biotechnology and Natural Resources (CABNR) Field Day. Two manuscripts were published in academic scientifc journals relating to this work which would reach an audience encompassing the worldwide scientifc community, in addition to anyone else interested in reading the material. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided?A Ph.D. student and a Master student were trained in cutting edge molecular biology techniques including animal care and feeding studies, gene expression analysis via qPCR, cell culture, western blotting, etc, during the course of these studies. How have the results been disseminated to communities of interest?The results from these studies have been disseminated to the scientific community via presentations at national meetings and publications in academic journals. The work was disseminated to the local lay community via outreach endeavors such as the annual CABNR Field Day. What do you plan to do during the next reporting period to accomplish the goals?The current project funding ended on June 30th 2015. We will continue to submit manuscripts resulting from the data generated during the funding period of this project.
Impacts
What was accomplished under these goals?
We have elucidated novel underlying molecular mechanisms that contribute to the hypotriglyceridemic action of GSPE. One study that was published in Molecular Nutrition and Food Research (featured on the cover of the April 2016 issue) determined that GSPE inhibits intestinal bile acid absorption by differentially modulating the expression of genes associated with bile acid uptake and transport in an FXR-dependent manner. These gene changes ultimately result in reduced uptake of bile acids from the intestinal lumen, leading to a reduction in the amount of bile acids being returned to the liver, and consequently increasing the amount excreted via the feces. The changes initiated in the intestine lead to increased conversion of cholesterol into bile acids to replenish those lost via the feces. The increased requirement for bile acid biosynthesis leads to a reduction in the intracellular cholesterol stores within the liver, which ultimately necessitates increased triglyceride catabolism to provide the building blocks to facilitate increased endogenous cholesterol synthesis and subsequently bile acids. The elucidation of this novel mechanism of action has provided a new insight into the molecular effects exerted by this natural compund, providing avenues for futher reserach as a hypolipidemic agent. A second study utilized the fructose-fed rat model to induce hypertriglyceridemia (high triglyceride (TG) levels) andc steatosis (fat accumulation within the liver). The results from this study were published in Plos One and demonstrate that GSPE exerts a significant TG-lowering effect in the rats fed fructose for 8 weeks prior to administration for 7 days with GSPE. Fructose induced a 171% increase in serum TG levels after 9 weeks compared to the control, which was ameliorated by treatment with GSPE, resulting in a 41% reduction. In addition, fructose induced microvesicular steatosis and increased heptic lipid accumulation, which was accompanied by mild inflammatory infiltration. GSPE treatment to the animals for one week while they remained on the fructose diet resulted in a significant decrease in heptic lipid volume density and therefore steatosis. At the molecular level, GSPE down-regulated the expression of genes associated with lipogenesis, increased hepatic cholesterol synthesis, but did not increase bile acid biosynthesis. Instead of channeling the newly synthesized cholesterol into bile acid biosynthesis, it was instead directed via transintestinal cholesterol efflux (TICE) for excretion via the feces. It is important to note that increased cholesterol in the liver, as well as lipid generated from the high-fructose diet, would worsen the grade of steatosis, therefore, GSPE exerts a unique protective mechanism to get rid of the cholesterol, as well as reducing lipogenesis, which could otherwise exacerbate the steatosis induced by fructose feeding. The results obtained from this study indicate that GSPE warrants further study as a treatment strategy against metabolic dysregulation and the potential for amelioration of hepatic steatosis. The third study (under review) was designed to determine the TG-lowering effect of GSPE in the presence of the bile acid sequestrant cholestyramine (CHY). Cholestyramine is a non-absorbable resin that binds bile acids in the intestinal lumen, causing them to be excreted in the feces. The lack of bile acids returning to the liver induces the conversion of cholesterol into bile acids, thereby exerting a hypocholesterolemic effect. This study provides novel and innovative insight into the molecular regulatory interactions between GSPE and CHY. GSPE exerts complementary actions in the presence of CHY by inducing bile acid biosynthesis, inhibiting uptake of bile acids produced in the process, and reducing hepatic lipogenesis. Consequently, GSPE may be valuable as a potential combinational therapy with CHY for the treatment of dyslipidemia.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2015
Citation:
A Grape Seed Procyanidin Extract Ameliorates Fructose-Induced Hypertriglyceridemia in Rats via Enhanced Fecal Bile Acid and Cholesterol Excretion and Inhibition of Hepatic Lipogenesis.
Downing LE, Heidker RM, Caiozzi GC, Wong BS, Rodriguez K, Del Rey F, Ricketts ML.
PLoS One. 2015 Oct 12;10(10):e0140267. doi:10.1371/journal.pone.0140267. eCollection 2015.
PMID:26458107
- Type:
Journal Articles
Status:
Published
Year Published:
2015
Citation:
Dietary procyanidins selectively modulate intestinal farnesoid X receptor-regulated gene expression to alter enterohepatic bile acid recirculation: elucidation of a novel mechanism to reduce triglyceridemia.
Heidker RM, Caiozzi GC, Ricketts ML.
Mol Nutr Food Res. 2015 Dec 31. doi: 10.1002/mnfr.201500795. [Epub ahead of print] PMID:26718753
- Type:
Journal Articles
Status:
Under Review
Year Published:
2016
Citation:
Grape Seed Procyanidins and Cholestyramine Differentially Alter Bile Acid and Cholesterol Homeostatic Gene Expression in Mouse Intestine and Liver
Rebecca M. Heidker, Gianella C. Caiozzi and Marie-Louise Ricketts
(Manuscript Under review in PLos One)
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2015
Citation:
Rebecca Heidker, Gianella Caiozzi, and Marie-Louise Ricketts
Co-administration of a Grape Seed Procyanidin Extract and the Bile Acid Sequestrant, Cholestyramine, Results in Beneficial Metabolic Alterations, Including Decreased Triglyceride Levels
FASEB J April 2015 29:271.5
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2016
Citation:
Dietary procyanidins lower serum triglyceride levels via up-regulation in Ppar alpha and its downstream target gene expression
Marie-Louise Ricketts, Ph.D. and Laura Downing
Faseb J April 2016 30:691.9
|
Progress 10/01/13 to 09/30/14
Outputs
Target Audience: During the past year we have presented an abstract based on our research at the annual Experimental Biology (EB) meeting in San Diego, CA. This meeting was targeted at research scientists in the disciplines of Nutrition, Anatomy, Physiology, Pathology and Pharmacology. EB is an annual meeting comprised of over 14,000 scientists. Our poster presentation was awarded 1st place in the pre-doctoral student category in the Dietary Bioactive Components Research Interest Section of the Amercian Society for Nutrition (ASN). Several students, both undergraduate and graduate, have been trained in molecular biology techniques associated with this project, thereby enhancing the education of undergraduate student workers, an Honors thesis undergraduate, and Ph.D and Master level graduate students. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided? This project has provided training opportunities for both undergraduate and graduate students. Undergraduate students have had the opportunity to gain experience via either employment as a student worker, volunteer work in the lab or by working on an honors thesis. Graduate students have also been provided with an opportunity to obtain training in molecular biology during the course of the past year. How have the results been disseminated to communities of interest? The results obtained this year have been presented at the annual Experimental Biology meeting to research scientists in the fields of Nutrition, Anatomy, Physiology and Pharmacology. A manuscript based on our results has been submitted for scientific peer review. An abstract has been submitted to EB 2015 and will be presented as an oral presentation. In addition we presented our results to the local community at the annual College of Agriculture, Biotechnology and Natural Resources (CABNR) Field day where members of the public had an opportunity to learn about our on-going research and were interested in the results and the important beneficial benefits of GSPE for counteracting metabolic dysregulation, such as high serum triglyceride and cholesterol, which are important factors to be targeted in the prevention of cardiovascular disease. What do you plan to do during the next reporting period to accomplish the goals? During the next reporting period, we plan to scale up the fractionation of the whole extract so that we can determine which components or components in the extract are responsible for the observed beneficial metabolic effects of GSPE which are mediated via FXR. In addition, we plan to complete on-going analysis of the gene regulatory effects of GSPE in a hyperlipidemic state in vivo in rodent models. We also plan to write and submit additional manuscripts based on the current on-going studies. Once the results are accepted in scientific journals, we will also write Factsheets that can then be distributed to the lay community both locally and nationally.
Impacts
What was accomplished under these goals?
During the past year we have continued our work to provide a clearer understanding regarding the molecular mechanisms by which grape seed procyanidin extract (GSPE) lowers serum triglyceride levels. We have extended our previous studies using human colonic cell lines and moved into testing wild type and farnesoid x receptor (FXR) knockout mice to determine the mechanism of action by GSPE in vivo. We have determined that GSPE selectively modulates intestinally regulated FXR genes important for bile acid absorption and transport, in an FXR-dependent manner, which ultimately causes decreased enterohepatic bile acid recirculation and increased fecal bile acid output. We have correlated gene regulatory effects occurring in both the intestine and liverwith decreased serum triglyceride and cholesterol levels, thereby elucidating a new mechanism. The results have been presented at the annual Experimental Biology meeting in 2014 and a manuscript has been submitted for review. In addition we have submitted an abstract to EB 2015, which has been selected for an oral presntation at the meeting to be held in March/April 2015. With resepct to Aim 3, we have started to fractionate the whole extract, and have been working to optimizie the fractionation process. We have used column chromatography to separate procyanidin components, which have then been dried under vacuum. The fractions have been run on TLC to determine whether they are monomers, dimers or trimers. So far we have collected mg quantities of monomer and dimer fractions, which we plan on assessing first via HPLC, for comparison with the whole extract. We plan on scaling up the fractionation process to facilitate increased yields and will then assess the potential for each fraction, alone or in combination, to transctivate FXR using in vitro assays and activity in vivo will subsequently be assessed.
Publications
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2014
Citation:
A grape seed procyanidin extract lowers serum triglyceride levels via selective modulation of intestinal FXR-target gene expression and inhibition of enterohepatic bile acid recirculation.
Rebecca Hintz, Gianella Caiozzi & Marie-Louise Ricketts
April 2014, The FASEB Journal Vol. 28 no. 1 Supplement 1045.35
|
Progress 10/01/12 to 09/30/13
Outputs
Target Audience: During the past year we have presented an abstract based on our research findings at the annual Endocrine Society meeting in San Franscisco. This meeting was targeted at both research scientists and medical professionals in the area of Endocrinology. Several students, both undergraduate and graduate students have been trained in techniques related to research in molecular biology/molecular nutrition based on this project, including undergraduate student workers, as well as master and PhD level stduents. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided? This project has provided training opportunities for both undergraduate and graduate students. Undergraduate students have had the opportunity to gain experience by either employment as a stduent worker, volunteer in the lab or by working on their honors thesis. Graduate stduents both at the Master and PhD level have also been provided with an opportunity to obtain training in molecular biology during the course of the past year. How have the results been disseminated to communities of interest? The results obtained so far have been presented as an abstract at the annual meeting of the Endocrine Society to research scientists and clinicians in the field of Endocrinology. What do you plan to do during the next reporting period to accomplish the goals? During the next reporting period, we plan to complete the studies relating to the investigation of the effects of GSPE on bile acid metabolism, as well as continuing to investigate other potential aspects of the molecular actions of GSPE. In addition,, we will investingate which component(s) in the extract mediate the observed effects.
Impacts
What was accomplished under these goals?
The outcomes of this project aim to provide a clearer understanding of the molecular mechanism by which GSPE reduces serum triglyceride levels. The impact that this research will have is related to providing a further insight into precisely how GSPE works to provide beneficial health effects. This year we have completed the in vitro studies using Caco2 cells (a human colonic cell line) to assess the intestine FXR-specific effects of GSPE and have moved forward with in vivo studies using wild type C57BL6 mice. The results from the in vivo studies strongly indicates that GSPE modifies FXR target genes involved in bile acid metabolism and homeostasis. Specifically, we have treated the cells for varying time points between 0 and 24hrs with either a bile acid, chenodeoxycholic acid (CDCA), varying doses of GSPE (20, 50 or 100mg/L) or a combination of both. We have identifed alterations in gene expression for bile acid transporters and bile acid binding proteins. The studies in vivo have also confirmed these in vitro observations. As a consequence of the alteration in these proteins important for bile acid homeostasis, we have also seen a corresponsing decrease in enterohepatic bile acid recirculation. We propose that these differences in gene expression ultimately contribute to the TG-lowering effect of this extract. We have also determined the effect of GSPE on TG levels in the presence and absence of cholestyramine (chol), a bile acid binding resin. We have found that treatment with both chol and GSPE augments the TG-lowering effects of chol administration alone. We currently have on-going studies to confirm the role of FXR in this effect by using FXR knockout mouse models.
Publications
- Type:
Conference Papers and Presentations
Status:
Published
Year Published:
2013
Citation:
A Grape Seed Procyanidin Extract as an Intestinal Selective Bile Acid Receptor Modulator. Gianella Caiozzi & Marie-Louise Ricketts Abstract # SUN-357. The Endocrine Society's 95th Annual meeting and Expo, San Francisco, June 15th-18th 2013
- Type:
Theses/Dissertations
Status:
Published
Year Published:
2013
Citation:
Understanding the role of the intestine in the molecular hypotriglyceridemic actions of a grape seed procyanidin extract.
A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science in Nutrition
By Gianella C Caiozzi
- Type:
Conference Papers and Presentations
Status:
Accepted
Year Published:
2014
Citation:
A grape seed procyanidin extract lowers serum triglyceride levels via selective modulation of intestinal FXR-target gene expression and inhibition of enterohepatic bile acid recirculation.
Rebecca Hintz, Gianella Caiozzi & Marie-Louise Ricketts
|
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