title: High glucose potentiates L-FABP mediated fibrate induction of PPARα in mouse hepatocytes.
abstract: Although liver fatty acid binding protein (L-FABP) binds fibrates and PPARα in vitro and enhances fibrate induction of PPARα in transformed cells, the functional significance of these findings is unclear, especially in normal hepatocytes. Studies with cultured primary mouse hepatocytes show that: 1) At physiological (6mM) glucose, fibrates (bezafibrate, fenofibrate) only weakly activated PPARα transcription of genes in LCFA β-oxidation; 2) High (11-20mM) glucose, but not maltose (osmotic control), significantly potentiated fibrate-induction of mRNA of these and other PPARα target genes to increase LCFA β-oxidation. These effects were associated with fibrate-mediated redistribution of L-FABP into nuclei-an effect prolonged by high glucose-but not with increased de novo fatty acid synthesis from glucose; 3) Potentiation of bezafibrate action by high glucose required an intact L-FABP/PPARα signaling pathway as shown with L-FABP null, PPARα null, PPARα inhibitor-treated WT, or PPARα-specific fenofibrate-treated WT hepatocytes. High glucose alone in the absence of fibrate was ineffective. Thus, high glucose potentiation of PPARα occurred through FABP/PPARα rather than indirectly through other PPARs or glucose induced signaling pathways. These data indicated L-FABP's importance in fibrate-induction of hepatic PPARα LCFA β-oxidative genes, especially in the context of high glucose levels.
authors.affiliation: Department of Physiology and Pharmacology, Texas A&M University, TVMC, College Station, TX 77843-4466, USA.
authors.forename: Anca D
authors.initials: AD
authors.lastname: Petrescu
authors.forename: Avery L
authors.initials: AL
authors.lastname: McIntosh
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Storey
authors.forename: Huan
authors.initials: H
authors.lastname: Huang
authors.forename: Gregory G
authors.initials: GG
authors.lastname: Martin
authors.forename: Danilo
authors.initials: D
authors.lastname: Landrock
authors.forename: Ann B
authors.initials: AB
authors.lastname: Kier
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Schroeder
mesh_terms: D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology*; D005947:Glucose / Q000494:pharmacology*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D051379:Mice; D008817:Mice, Mutant Strains; D010084:Oxidation-Reduction / Q000187:drug effects; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013549:Sweetening Agents / Q000494:pharmacology*
chemical_list: C493320:Fabp1 protein, mouse; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D013549:Sweetening Agents; D005947:Glucose; D011345:Fenofibrate; D001629:Bezafibrate