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Two farnesoid X receptor alpha isoforms in Japanese medaka (Oryzias latipes) are differentially activated in vitro.

ABSTRACT: The nuclear receptor farnesoid X receptor alpha (FXRalpha, NR1H4) is activated by bile acids in multiple species including mouse, rat, and human and in this study we have identified two isoforms of Fxralpha in Japanese medaka (Oryzias latipes), a small freshwater teleost. Both isoforms share a high amino acid sequence identity to mammalian FXRalpha (approximately 70% in the ligand-binding domain). Fxralpha1 and Fxralpha2 differ within the AF1 domain due to alternative splicing at the fourth intron-exon boundary. This process results in Fxralpha1 having an extended N-terminus compared to Fxralpha2. A Gal4DBD-FxralphaLBD fusion construct was activated by chenodeoxycholic, cholic, deoxycholic and lithocholic acids, and the synthetic agonist GW4064 in transient transactivation assays. Activation of the Gal4DBD-FxralphaLBD fusion construct was enhanced by addition of PGC-1alpha, as demonstrated through titration assays. Surprisingly, when the full-length versions of the two Fxralpha isoforms were compared in transient transfection assays, Fxralpha2 was activated by C(24) bile acids and GW4064, while Fxralpha1 was not significantly activated by any of the compounds tested. Since the only significant difference between the full-length constructs was sequence in the AF1 domain, these experiments highlight a key functional region in the Fxralpha AF1 domain. Furthermore, mammalian two-hybrid studies demonstrated the ability of Fxralpha2, but not Fxralpha1, to interact with PGC-1alpha and SRC-1, and supported our results from the transient transfection reporter gene activation assays. These data demonstrate that both mammalian and teleost FXR (Fxralpha2 isoform) are activated by primary and secondary bile acids.

SUBMITTER: Howarth DL

PROVIDER: S-EPMC2874645 | biostudies-literature | 2010 Jul

REPOSITORIES: biostudies-literature

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Two farnesoid X receptor alpha isoforms in Japanese medaka (Oryzias latipes) are differentially activated in vitro.

Howarth Deanna L DL Hagey Lee R LR Law Sheran H W SHW Ai Ni N Krasowski Matthew D MD Ekins Sean S Moore John T JT Kollitz Erin M EM Hinton David E DE Kullman Seth W SW

Aquatic toxicology (Amsterdam, Netherlands) 20100301 3

The nuclear receptor farnesoid X receptor alpha (FXRalpha, NR1H4) is activated by bile acids in multiple species including mouse, rat, and human and in this study we have identified two isoforms of Fxralpha in Japanese medaka (Oryzias latipes), a small freshwater teleost. Both isoforms share a high amino acid sequence identity to mammalian FXRalpha (approximately 70% in the ligand-binding domain). Fxralpha1 and Fxralpha2 differ within the AF1 domain due to alternative splicing at the fourth intr ...[more]

PMID: 20430454

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Project description:Intraspecific trait variation has large effects on the ecosystem and is greatly affected by human activities. To date, most studies focused on single-trait analyses, while considering multiple traits is expected to better predict how an individual interacts with its environment. Here, we used a mesocosm experiment with fish Oryzias latipes to test whether individual growth, boldness and functional traits (feeding rate and stoichiometric traits) formed one functional pace-of-life syndrome (POLS). We then tested the effects of among-individual mean and variance of fish functional POLSs within mesocosms on invertebrate community (e.g. zoobenthos and zooplankton abundances) and ecosystem processes (e.g. ecosystem metabolism, algae stock, nutrient concentrations). Stoichiometric traits correlated with somatic growth and behaviours, forming two independent functional POLS (i.e. two major covariance axes). Mean values of the first syndrome were sex- and environment-dependent and were associated with (i) long-term (10 generations; 4 years) selection for small or large body size resulting in contrasting life histories and (ii) short-term (6 weeks) effects of experimental treatments on resource availability (through manipulation of light intensity and interspecific competition). Specifically, females and individuals from populations selected for a small body size presented fast functional POLS with faster growth rate, higher carbon body content and lower boldness. Individuals exposed to low resources (low light and high competition) displayed a slow functional POLS. Higher mesocosm mean and variance values in the second functional POLS (i.e. high feeding rate, high carbon:nitrogen body ratio, low ammonium excretion rate) were associated to decreased prey abundances, but did not affect any of the ecosystem processes. We highlighted the presence of functional multi-trait covariation in medaka, which were affected by sex, long-term selection history and short-term environmental conditions, that ultimately had cascading ecological consequences. We stressed the need for applying this approach to better predict ecosystem response to anthropogenic global changes.

Dataset Information

Two farnesoid X receptor alpha isoforms in Japanese medaka (Oryzias latipes) are differentially activated in vitro.

Publications

Two farnesoid X receptor alpha isoforms in Japanese medaka (Oryzias latipes) are differentially activated in vitro.

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