Comparative Transcriptional Network Modeling of Three PPAR-α/γ Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes
Aims: To compare the molecular and biologic signatures of a balanced dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist, aleglitazar, with tesaglitazar (a dual PPAR-α/γ agonist) or a combination of pioglitazone (Pio; PPAR-γ agonist) and fenofibrate (Feno; PPAR-α agonist) in human...
| Main Authors: | , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | en_US |
| Published: |
Public Library of Science
2012
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| Online Access: | http://hdl.handle.net/1721.1/71740 |
| _version_ | 1826214912694681600 |
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| author | Deehan, Renee Maerz-Weiss, Pia Catlett, Natalie L. Steiner, Guido Wong, Ben Wright, Matthew B. Blander, Gil Elliston, Keith O. Ladd, William Bobadilla, Maria Mizrahi, Jacques Haefliger, Carolina Edgar, Alan |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Deehan, Renee Maerz-Weiss, Pia Catlett, Natalie L. Steiner, Guido Wong, Ben Wright, Matthew B. Blander, Gil Elliston, Keith O. Ladd, William Bobadilla, Maria Mizrahi, Jacques Haefliger, Carolina Edgar, Alan |
| author_sort | Deehan, Renee |
| collection | MIT |
| description | Aims:
To compare the molecular and biologic signatures of a balanced dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist, aleglitazar, with tesaglitazar (a dual PPAR-α/γ agonist) or a combination of pioglitazone (Pio; PPAR-γ agonist) and fenofibrate (Feno; PPAR-α agonist) in human hepatocytes.
Methods and Results:
Gene expression microarray profiles were obtained from primary human hepatocytes treated with EC50-aligned low, medium and high concentrations of the three treatments. A systems biology approach, Causal Network Modeling, was used to model the data to infer upstream molecular mechanisms that may explain the observed changes in gene expression. Aleglitazar, tesaglitazar and Pio/Feno each induced unique transcriptional signatures, despite comparable core PPAR signaling. Although all treatments inferred qualitatively similar PPAR-α signaling, aleglitazar was inferred to have greater effects on high- and low-density lipoprotein cholesterol levels than tesaglitazar and Pio/Feno, due to a greater number of gene expression changes in pathways related to high-density and low-density lipoprotein metabolism. Distinct transcriptional and biologic signatures were also inferred for stress responses, which appeared to be less affected by aleglitazar than the comparators. In particular, Pio/Feno was inferred to increase NFE2L2 activity, a key component of the stress response pathway, while aleglitazar had no significant effect. All treatments were inferred to decrease proliferative signaling.
Conclusions:
Aleglitazar induces transcriptional signatures related to lipid parameters and stress responses that are unique from other dual PPAR-α/γ treatments. This may underlie observed favorable changes in lipid profiles in animal and clinical studies with aleglitazar and suggests a differentiated gene profile compared with other dual PPAR-α/γ agonist treatments. |
| first_indexed | 2024-09-23T16:12:14Z |
| format | Article |
| id | mit-1721.1/71740 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:12:14Z |
| publishDate | 2012 |
| publisher | Public Library of Science |
| record_format | dspace |
| spelling | mit-1721.1/717402022-10-02T07:04:32Z Comparative Transcriptional Network Modeling of Three PPAR-α/γ Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes Deehan, Renee Maerz-Weiss, Pia Catlett, Natalie L. Steiner, Guido Wong, Ben Wright, Matthew B. Blander, Gil Elliston, Keith O. Ladd, William Bobadilla, Maria Mizrahi, Jacques Haefliger, Carolina Edgar, Alan Massachusetts Institute of Technology. Department of Biology Blander, Gil Blander, Gil Aims: To compare the molecular and biologic signatures of a balanced dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist, aleglitazar, with tesaglitazar (a dual PPAR-α/γ agonist) or a combination of pioglitazone (Pio; PPAR-γ agonist) and fenofibrate (Feno; PPAR-α agonist) in human hepatocytes. Methods and Results: Gene expression microarray profiles were obtained from primary human hepatocytes treated with EC50-aligned low, medium and high concentrations of the three treatments. A systems biology approach, Causal Network Modeling, was used to model the data to infer upstream molecular mechanisms that may explain the observed changes in gene expression. Aleglitazar, tesaglitazar and Pio/Feno each induced unique transcriptional signatures, despite comparable core PPAR signaling. Although all treatments inferred qualitatively similar PPAR-α signaling, aleglitazar was inferred to have greater effects on high- and low-density lipoprotein cholesterol levels than tesaglitazar and Pio/Feno, due to a greater number of gene expression changes in pathways related to high-density and low-density lipoprotein metabolism. Distinct transcriptional and biologic signatures were also inferred for stress responses, which appeared to be less affected by aleglitazar than the comparators. In particular, Pio/Feno was inferred to increase NFE2L2 activity, a key component of the stress response pathway, while aleglitazar had no significant effect. All treatments were inferred to decrease proliferative signaling. Conclusions: Aleglitazar induces transcriptional signatures related to lipid parameters and stress responses that are unique from other dual PPAR-α/γ treatments. This may underlie observed favorable changes in lipid profiles in animal and clinical studies with aleglitazar and suggests a differentiated gene profile compared with other dual PPAR-α/γ agonist treatments. 2012-07-20T19:11:07Z 2012-07-20T19:11:07Z 2012-04 2011-10 Article http://purl.org/eprint/type/JournalArticle 1932-6203 http://hdl.handle.net/1721.1/71740 Deehan, Renée et al. “Comparative Transcriptional Network Modeling of Three PPAR-α/γ Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes.” Ed. Zhi Xie. PLoS ONE 7.4 (2012): e35012. en_US http://dx.doi.org/10.1371/journal.pone.0035012 PLoS ONE Creative Commons Attribution http://creativecommons.org/licenses/by/2.5/ application/pdf Public Library of Science PLoS |
| spellingShingle | Deehan, Renee Maerz-Weiss, Pia Catlett, Natalie L. Steiner, Guido Wong, Ben Wright, Matthew B. Blander, Gil Elliston, Keith O. Ladd, William Bobadilla, Maria Mizrahi, Jacques Haefliger, Carolina Edgar, Alan Comparative Transcriptional Network Modeling of Three PPAR-α/γ Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes |
| title | Comparative Transcriptional Network Modeling of Three PPAR-α/γ Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes |
| title_full | Comparative Transcriptional Network Modeling of Three PPAR-α/γ Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes |
| title_fullStr | Comparative Transcriptional Network Modeling of Three PPAR-α/γ Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes |
| title_full_unstemmed | Comparative Transcriptional Network Modeling of Three PPAR-α/γ Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes |
| title_short | Comparative Transcriptional Network Modeling of Three PPAR-α/γ Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes |
| title_sort | comparative transcriptional network modeling of three ppar α γ co agonists reveals distinct metabolic gene signatures in primary human hepatocytes |
| url | http://hdl.handle.net/1721.1/71740 |
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