title: Short chain fatty acids regulate tyrosine hydroxylase gene expression through a cAMP-dependent signaling pathway.
abstract: Multiple intracellular and extracellular regulatory factors affect transcription of the tyrosine hydroxylase (TH) gene encoding the rate-limiting enzyme in the biosynthesis of the neurotransmitters dopamine, norepinephrine and epinephrine. Short chain fatty acids like butyrate are known to alter TH gene expression, but the mechanism of action is unknown. In this report, transient transfection assays identified the proximal TH promoter to contain sufficient genetic information to confer butyrate responsiveness to a reporter gene. Deletion studies and gel shift analyses revealed that the promoter region spanning the cAMP response element is an absolute requirement for transcriptional activation by butyrate. The branched short chain fatty acid valproate is used for seizure control in humans. Significantly, it has a similar aliphatic structure to butyrate, and it was found to have similar effects on TH in PC12 cells. Site-directed mutagenesis indicated that the effects of both fatty acids were mediated through the canonical CRE. Butyrate treatment also resulted in CREB phosphorylation without changing CREB protein levels. The increased phosphorylation of CREB correlated with accumulation of TH mRNA. The adenylate cyclase inhibitor dideoxyadenosine blocked both CREB phosphorylation and accumulation of TH mRNA. The data are consistent with the conclusion that butyrate induces post-translational modifications of pre-existing CREB molecules in a cAMP/PKA-dependent manner to alter TH transcription. These results support the role of butyrate as a novel exogenous regulatory factor in TH gene expression. Our data delineate a molecular mechanism through which diet-derived environmental signals (e.g. butyrate) can modulate catecholaminergic systems by affecting TH gene transcription.
authors.affiliation: Department of Pediatrics, New York Medical College, Valhalla, NY 10595, USA.
authors.forename: Manuel
authors.initials: M
authors.lastname: DeCastro
authors.forename: Bistra B
authors.initials: BB
authors.lastname: Nankova
authors.forename: Parul
authors.initials: P
authors.lastname: Shah
authors.forename: Pranav
authors.initials: P
authors.lastname: Patel
authors.forename: Pradeep V
authors.initials: PV
authors.lastname: Mally
authors.forename: Ravi
authors.initials: R
authors.lastname: Mishra
authors.forename: Edmund F
authors.initials: EF
authors.lastname: La Gamma
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D015153:Blotting, Western / Q000379:methods; D002087:Butyrates / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005232:Fatty Acids, Volatile / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D008156:Luciferases / Q000378:metabolism; D016297:Mutagenesis, Site-Directed / Q000379:methods; D016716:PC12 Cells; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013997:Time Factors; D014162:Transfection / Q000379:methods; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D002087:Butyrates; D004791:Enzyme Inhibitors; D005232:Fatty Acids, Volatile; D014635:Valproic Acid; D000242:Cyclic AMP; D008156:Luciferases; D014446:Tyrosine 3-Monooxygenase