ABSTRACT
The molecular mechanisms occurring in the nervous system that underlie behavioral responses to ethanol remain poorly understood. Here, we report that molecular requirements for two of these responses, initial sensitivity and the development of rapid tolerance, comap to the same small set of neurons. We show that null homer mutant flies exhibit both increased sensitivity to the sedative effects of ethanol and failure to develop normal levels of rapid tolerance. Both the sensitivity and rapid tolerance phenotypes of the homer mutants are rescued by the expression of wild-type homer in a subset of neurons that include the ellipsoid body. Thus, some of the molecular- and systems-level requirements for these two behavioral responses to ethanol are identical.
Subject(s)
Carrier Proteins/physiology , Central Nervous System Depressants/pharmacology , Drosophila Proteins/physiology , Drug Tolerance/genetics , Ethanol/pharmacology , Neurons/physiology , Animals , Animals, Genetically Modified , Brain/cytology , Brain/drug effects , Brain/physiology , Carrier Proteins/genetics , Central Nervous System Depressants/pharmacokinetics , DNA-Binding Proteins , Drosophila Proteins/genetics , Drosophila melanogaster , Drug Resistance/genetics , Ethanol/pharmacokinetics , Homer Scaffolding Proteins , Male , Neurons/drug effects , Oligonucleotide Array Sequence Analysis , Phenotype , Saccharomyces cerevisiae Proteins/genetics , Transcription Factors/geneticsABSTRACT
The resin of the Commiphora mukul tree has been used in Ayurvedic medicine for more than 2000 years to treat a variety of ailments. Studies in both animal models and humans have shown that this resin, termed gum guggul, can decrease elevated lipid levels. The stereoisomers E- and Z-guggulsterone have been identified as the active agents in this resin. Recent studies have shown that these compounds are antagonist ligands for the bile acid receptor farnesoid X receptor (FXR), which is an important regulator of cholesterol homeostasis. It is likely that this effect accounts for the hypolipidemic activity of these phytosteroids.
Subject(s)
Cholesterol/metabolism , Hyperlipidemias/drug therapy , Hypolipidemic Agents/pharmacology , Plant Extracts/pharmacology , Animals , Cholesterol, Dietary/administration & dosage , Commiphora , DNA-Binding Proteins/metabolism , Disease Models, Animal , Humans , Hypolipidemic Agents/adverse effects , Hypolipidemic Agents/therapeutic use , Plant Extracts/adverse effects , Plant Extracts/therapeutic use , Plant Gums , Receptors, Cytoplasmic and Nuclear , Transcription Factors/metabolismABSTRACT
BACKGROUND & AIMS: In the rat, an increase in ileal bile acid binding protein (IBABP) expression occurs during the third postnatal week. In vitro studies suggest that bile acids (BAs) increase IBABP transcription by activating the BA receptor, farnesoid X receptor (FXR). Thus, we investigated the role of BAs on the ontogenic expression of IBABP and whether FXR may mediate these effects. METHODS: Suckling rats were gavage-fed taurocholate for 3 days or were allowed to develop normally. Ileums were collected for Northern and Western blot analyses. Electrophoretic mobility shift assays for functional FXR were performed using nuclear extracts from ileums of both adult and developing rats. RESULTS: Taurocholate gavage significantly elevated IBABP messenger RNA and protein levels in suckling animals. Gelshift assays using adult ileal nuclear extracts incubated with a radiolabeled consensus inverted repeat-1 oligonucleotide (response element for FXR) revealed a high-molecular weight DNA/protein complex. Cold competition and supershift assays showed that this complex is sequence specific and confirmed that FXR is a component of the complex. Gelshift assays with nuclear extracts from rat ileum at different ages revealed absence of the DNA/protein complex in the second postnatal week when there is lack of IBABP expression and presence of these complexes at later ages when there is normally high expression. Western blot analyses showed FXR and its heterodimer partner, retinoid X receptor alpha, protein levels are low in the ileum during the suckling period and increase during the third postnatal week. CONCLUSIONS: BAs play a role in the normal developmental expression of IBABP through FXR activation, and decreased functional FXR in ileal nuclei during the suckling period may account, in part, for the lack of IBABP expression at this time.
Subject(s)
Bile Acids and Salts/pharmacology , Carrier Proteins/genetics , DNA-Binding Proteins/physiology , Gene Expression Regulation/drug effects , Hydroxysteroid Dehydrogenases , Ileum/metabolism , Membrane Glycoproteins , Transcription Factors/physiology , Animals , Male , RNA, Messenger/analysis , Rats , Rats, Sprague-Dawley , Receptors, Cytoplasmic and Nuclear , Receptors, Retinoic Acid/physiology , Retinoid X ReceptorsABSTRACT
Extracts of the resin of the guggul tree (Commiphora mukul) lower LDL (low-density lipoprotein) cholesterol levels in humans. The plant sterol guggulsterone [4,17(20)-pregnadiene-3,16-dione] is the active agent in this extract. We show that guggulsterone is a highly efficacious antagonist of the farnesoid X receptor (FXR), a nuclear hormone receptor that is activated by bile acids. Guggulsterone treatment decreases hepatic cholesterol in wild-type mice fed a high-cholesterol diet but is not effective in FXR-null mice. Thus, we propose that inhibition of FXR activation is the basis for the cholesterol-lowering activity of guggulsterone. Other natural products with specific biologic effects may modulate the activity of FXR or other relatively promiscuous nuclear hormone receptors.
