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Series GSE73035 Query DataSets for GSE73035
Status Public on Sep 28, 2015
Title Bioenergetic cues shift FXR splicing towards FXRα2 to modulate hepatic lipolysis and fatty acid metabolism
Organism Mus musculus
Experiment type Expression profiling by array
Summary Farnesoid X receptor (FXR) plays a prominent role in hepatic lipid metabolism. The FXR gene encodes four proteins with structural differences suggestive of discrete biological functions about which little is known. We show that FXR isoforms have specific effects on hepatic metabolism and uncover novel pathways under their control. Gene expression profiling of hepatocytes expressing each FXR variant revealed large differences in their target gene sets. Notably, FXRα2 (but not α1) activates a broad transcriptional program in hepatocytes conducive to lipolysis, fatty acid oxidation, and ketogenesis. Consequently, FXRα2 decreases cellular lipid accumulation and improves insulin sensitivity. FXRα2 expression in Fxr-/- mouse liver activates a similar gene program and robustly decreases hepatic triglyceride levels. On the other hand, FXRα1 reduces hepatic triglyceride content to a lesser extent and does so through regulation of lipogenic gene expression. Bioenergetic cues, such as fasting and exercise, dynamically regulate Fxr splicing in mouse liver to increase Fxrα2 expression. Our results show that the main FXR variants in human liver (α1 and α2) reduce hepatic lipid accumulation through distinct mechanisms and to different degrees. Thus, pharmacological or lifestyle interventions, such as exercise, aimed at modulating hepatic FXR splicing may improve the therapeutic efficacy of FXR agonists.
 
Overall design Primary hepatocytes from male C57BL/6J mice were isolated, cultured and transduced as previously described (Estall et al. 2009). To evaluate the gene programs regulated by each FXR isoform, we generated recombinant adenoviruses expressing each human FXR variant (FXRα1, α2, α3, and α4). All adenoviruses also express GFP from an independent CMV promoter. An adenovirus expressing GFP alone was used as a control. Hepatocytes were transduced overnight with each adenovirus and processed for RNA extraction 36 h post-transduction.
 
Contributor(s) Correia JC, Massart J, de Boer JF, Porsmyr-Palmertz M, Martínez-Redondo V, Agudelo LZ, Sinha I, Meierhofer D, Ribeiro V, Björnholm M, Sauer S, Dahlman-Wright K, Zierath JR, Groen AK, Ruas JL
Citation(s) 26909306
Jorge C. Correia, Julie Massart, Jan Freark de Boer, Margareta Porsmyr-Palmertz, Vicente Martínez-Redondo, Leandro Z. Agudelo, Indranil Sinha, David Meierhofer, Vera Ribeiro, Marie Björnholm, Sascha Sauer, Karin Dahlman-Wright, Juleen R. Zierath, Albert K. Groen, Jorge L. Ruas. Bioenergetic cues shift FXR splicing towards FXRa2 to modulate hepatic lipolysis and fatty acid metabolism. Molecular Metabolism, Volume 4, Issue 12, 891 - 902; http://dx.doi.org/10.1016/j.molmet.2015.09.005
Submission date Sep 15, 2015
Last update date Jul 03, 2019
Contact name Karin Dahlman-Wright
Organization name Karolinska Institutet
Department Department of Biosciences and Nutrition
Lab Medicinaren 25/Neo
Street address Blickagången 16
City Huddinge
ZIP/Postal code 14157
Country Sweden
 
Platforms (1)
GPL11533 [MoGene-1_1-st] Affymetrix Mouse Gene 1.1 ST Array [transcript (gene) version]
Samples (15)
GSM1881075 FXRα1_1
GSM1881076 FXRα1_2
GSM1881077 FXRα1_3
Relations
BioProject PRJNA296011

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE73035_RAW.tar 68.5 Mb (http)(custom) TAR (of CEL)
Processed data included within Sample table

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