Search

Metabolic nuclear receptors are ligand-activated transcription factors which control a wide range of metabolic processes and signaling pathways in response to nutrients and xenobiotics. Targeting these NRs is at the forefront of our endeavours to generate novel treatment options for diabetes, metabolic syndrome and fatty liver disease. Numerous splice variants have been described for these metabolic receptors. Structural changes, as a result of alternative splicing, lead to functional differences among NR isoforms, resulting in the regulation of different metabolic pathways by these NR splice variants. In this review, we describe known splice variants of FXR, LXRs, PXR, RXR, LRH-1, CAR and PPARs. We discuss their structure and functions, and elaborate on the regulation of splice variant abundance by nutritional signals. We conclude that NR splice variants pose an intriguing new layer of complexity in metabolic signaling, which needs to be taken into account in the development of treatment strategies for metabolic diseases., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

The Farnesoid X receptor (FXR) is a nuclear receptor which is activated by bile acids. Bile acids function in solubilization of dietary fats and vitamins in the intestine. In addition, bile acids have been increasingly recognized to act as signaling molecules involved in energy metabolism pathways, amongst others via activating FXR. Upon activation by bile acids, FXR controls the expression of many genes involved in bile acid, lipid, glucose and amino acid metabolism. An inability to properly use and store energy substrates may predispose to metabolic disorders, such as obesity, diabetes, cholestasis and non-alcoholic fatty liver disease. These diseases arise through a complex interplay between genetics, environment and nutrition. Due to its function in metabolism, FXR is an attractive treatment target for these disorders. The regulation of FXR expression and activity occurs both at the transcriptional and at the post-transcriptional level. It has been shown that FXR can be phosphorylated, SUMOylated and acetylated, amongst other modifications, and that these modifications have functional consequences for DNA and ligand binding, heterodimerization and subcellular localization of FXR. In addition, these post-translational modifications may selectively increase or decrease transcription of certain target genes. In this review, we provide an overview of the posttranslational modifications of FXR and discuss their potential involvement in cholestatic and metabolic disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Appelman, van der Veen and van Mil.)