title: Stereospecific regulation of tyrosine hydroxylase and proenkephalin genes by short-chain fatty acids in rat PC12 cells.
abstract: Circulating short-chain fatty acids (SCFAs) are primarily derived from bacterial fermentation of carbohydrates in the colon where they function as physiologic modulators of epithelial cell maturation. Butyrate has been shown to induce tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis, and enkephalin neuropeptide gene transcription, suggesting a role in perinatal sympathoadrenal stress-adaptation. We sought to determine whether there were SCFA structural requirements for this effect. Nine biologically relevant SCFAs and butyrate derivatives were tested in an in vitro model (PC12, rat pheochromocytoma cells) for their ability to regulate neurotransmitter-related gene expression. Our results revealed that among all the studied SCFAs, only propionate and butyrate increased tyrosine hydroxylase and proenkephalin mRNA levels. The functional activity was selective to the carbon atom chain length and associated with the presence of an ethyl moiety in the carbon atom backbone chain. Modifications or absence of this domain affected the gene induction response, suggesting a receptor-mediated mechanism(s). Moreover, propionate, butyrate, and the drug 4-phenylbutyrate were each shown to regulate transmitter genes via at least three independent mechanisms: histone hyperacetylation, cAMP signaling, or peroxisome proliferator-activated receptor gamma-mediated pathways. Thus, the biologic impact of SCFAs on catecholaminergic and opioid systems depend on the activation of SCFA-specific, dose-specific, and gene-specific molecular mechanisms. We speculate that 1) circulating levels of SCFAs may influence sympathoadrenal transmitter biosynthesis and hence whole animal stress-adaptive responsiveness after birth, and 2) the adverse effects of antibiotics on delayed acquisition of postnatal gut flora may affect this apparent evolutionary advantage of gut colonization.
authors.affiliation: The Regional Neonatal Center, Westchester Medical Center, New York Medical College, Valhalla, New York 10595, USA.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Mally
authors.forename: Ravi
authors.initials: R
authors.lastname: Mishra
authors.forename: Swati
authors.initials: S
authors.lastname: Gandhi
authors.forename: Manuel H
authors.initials: MH
authors.lastname: Decastro
authors.forename: Bistra B
authors.initials: BB
authors.lastname: Nankova
authors.forename: Edmund F
authors.initials: EF
authors.lastname: Lagamma
mesh_terms: D000107:Acetylation; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002843:Chromatin / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004745:Enkephalins / Q000096:biosynthesis* / Q000737:chemistry; D005232:Fatty Acids, Volatile / Q000378:metabolism*; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D016716:PC12 Cells; D010654:Phenylbutyrates / Q000378:metabolism; D011498:Protein Precursors / Q000096:biosynthesis* / Q000737:chemistry; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013237:Stereoisomerism; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis* / Q000737:chemistry
chemical_list: D002843:Chromatin; D004745:Enkephalins; D005232:Fatty Acids, Volatile; D006657:Histones; D018377:Neurotransmitter Agents; D010654:Phenylbutyrates; D011498:Protein Precursors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C029992:proenkephalin; C075773:4-phenylbutyric acid; D000242:Cyclic AMP; D014446:Tyrosine 3-Monooxygenase