title: Comparative transcriptional network modeling of three PPAR-α/γ co-agonists reveals distinct metabolic gene signatures in primary human hepatocytes.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  Gene expression microarray profiles were obtained from primary human hepatocytes treated with EC(50)-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.
authors.affiliation: Selventa, Cambridge, Massachusetts, United States of America.
authors.forename: Renée
authors.initials: R
authors.lastname: Deehan
authors.forename: Pia
authors.initials: P
authors.lastname: Maerz-Weiss
authors.forename: Natalie L
authors.initials: NL
authors.lastname: Catlett
authors.forename: Guido
authors.initials: G
authors.lastname: Steiner
authors.forename: Ben
authors.initials: B
authors.lastname: Wong
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Wright
authors.forename: Gil
authors.initials: G
authors.lastname: Blander
authors.forename: Keith O
authors.initials: KO
authors.lastname: Elliston
authors.forename: William
authors.initials: W
authors.lastname: Ladd
authors.forename: Maria
authors.initials: M
authors.lastname: Bobadilla
authors.forename: Jacques
authors.initials: J
authors.lastname: Mizrahi
authors.forename: Carolina
authors.initials: C
authors.lastname: Haefliger
authors.forename: Alan
authors.initials: A
authors.lastname: Edgar
mesh_terms: D000476:Alkanesulfonates / Q000494:pharmacology*; D002478:Cells, Cultured; D011345:Fenofibrate / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D010080:Oxazoles / Q000494:pharmacology*; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D010666:Phenylpropionates / Q000494:pharmacology*; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D000476:Alkanesulfonates; D010080:Oxazoles; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; D045162:Thiazolidinediones; D013876:Thiophenes; C542437:aleglitazar; C501413:tesaglitazar; D011345:Fenofibrate; D000077205:Pioglitazone