title: Stimulation of astrocyte fatty acid oxidation by thyroid hormone is protective against ischemic stroke-induced damage.
abstract: We previously demonstrated that stimulation of astrocyte mitochondrial ATP production via P2Y1receptor agonists was neuroprotective after cerebral ischemic stroke. Another mechanism that increases ATP production is fatty acid oxidation (FAO). We show that in primary human astrocytes, FAO and ATP production are stimulated by 3,3,5 triiodo-l-thyronine (T3). We tested whether T3-stimulated FAO enhances neuroprotection, and show that T3 increased astrocyte survival after either hydrogen peroxide exposure or oxygen glucose deprivation. T3-mediated ATP production and protection were both eliminated with etomoxir, an inhibitor of FAO. T3-mediated protection in vitro was also dependent on astrocytes expressing HADHA (hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase), which we previously showed was critical for T3-mediated FAO in fibroblasts. Consistent with previous reports, T3-treatment decreased stroke volumes in mice. While T3 decreased stroke volume in etomoxir-treated mice, T3 had no protective effect on stroke volume in HADHA +/- mice or in mice unable to upregulate astrocyte-specific energy production. In vivo, 95% of HADHA co-localize with glial-fibrillary acidic protein, suggesting the effect of HADHA is astrocyte mediated. These results suggest that astrocyte-FAO modulates lesion size and is required for T3-mediated neuroprotection post-stroke. To our knowledge, this is the first report of a neuroprotective role for FAO in the brain.
authors.affiliation: 1 Department of Neurosurgery, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Naomi L
authors.initials: NL
authors.lastname: Sayre
authors.affiliation: 2 Department of Cellular & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Mikaela
authors.initials: M
authors.lastname: Sifuentes
authors.affiliation: 2 Department of Cellular & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: Deborah
authors.initials: D
authors.lastname: Holstein
authors.affiliation: 3 Gene Regulation Section, Laboratory of Molecular Biology, National Institutes of Health, Bethesda, MD, 20892.
authors.forename: Sheue-Yann
authors.initials: SY
authors.lastname: Cheng
authors.affiliation: 3 Gene Regulation Section, Laboratory of Molecular Biology, National Institutes of Health, Bethesda, MD, 20892.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Zhu
authors.affiliation: 2 Department of Cellular & Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.|4 Department of Cellular & Structural Biology, South Texas Research Facility Neuroscience Center, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Lechleiter
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D063992:Mitochondrial Trifunctional Protein, alpha Subunit / Q000032:analysis / Q000378:metabolism; D000066829:Neuroprotection / Q000187:drug effects; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use*; D010084:Oxidation-Reduction / Q000187:drug effects*; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014284:Triiodothyronine / Q000378:metabolism / Q000627:therapeutic use*
chemical_list: D005227:Fatty Acids; D005904:Glial Fibrillary Acidic Protein; D018696:Neuroprotective Agents; D014284:Triiodothyronine; D000255:Adenosine Triphosphate; D063992:Mitochondrial Trifunctional Protein, alpha Subunit; C576214:Hadha protein, mouse
keywords: Astrocyte; fatty acid oxidation; neuroprotection; stroke; thyroid hormone