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Bioenergetic cues shift FXR splicing towards FXRα2 to modulate hepatic lipolysis and fatty acid metabolism

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Meierhofer,  David
Mass Spectrometry (Head: David Meierhofer), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Sauer,  Sascha
Nutrigenomics and Gene Regulation (Sascha Sauer), Independent Junior Research Groups (OWL), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Citation

Correia, J. C., Massart, J., de Boer, J. F., Porsmyr-Palmertz, M., Martínez-Redondo, V., Agudelo, L. Z., et al. (2015). Bioenergetic cues shift FXR splicing towards FXRα2 to modulate hepatic lipolysis and fatty acid metabolism. Molecular Metabolism, 4(12), 891-901. doi:10.1016/j.molmet.2015.09.005.


Cite as: https://hdl.handle.net/11858/00-001M-0000-0029-BE59-B
Abstract
Objective: 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. Methods: We expressed each FXR variant in primary hepatocytes and evaluated global gene expression, lipid pro fi le, and metabolic fl uxes. Gene delivery of FXR variants to Fxr / mouse liver was performed to evaluate their role in vivo . The effects of fasting and physical exercise on hepatic Fxr splicing were determined. Results: We show that FXR splice isoforms regulate largely different gene sets and have speci fi c effects on hepatic metabolism. FXR a 2 (but not a 1) activates a broad transcriptional program in hepatocytes conducive to lipolysis, fatty acid oxidation, and ketogenesis. Consequently, FXR a 2 decreases cellular lipid accumulation and improves cellular insulin signaling to AKT. FXR a 2 expression in Fxr / mouse liver activates a similar gene program and robustly decreases hepatic triglyceride levels. On the other hand, FXR a 1 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 Fxr a 2 expression. Conclusions: Our results show that the main FXR variants in human liver ( a 1 and a 2) reduce hepatic lipid accumulation through distinct mechanisms and to different degrees. Taking this novel mechanism into account could greatly improve the pharmacological targeting and therapeutic ef fi cacy of FXR agonists.