Posttranslational Modifications of Lipid-Activated Nuclear Receptors: Focus on Metabolism

Abstract

Posttranslational modifications (PTMs) occur to nearly all proteins, are catalyzed by specific enzymes, and are subjected to tight regulation. They have been shown to be a powerful means by which the function of proteins can be modified, resulting in diverse effects. Technological advances such as the increased sensitivity of mass spectrometry–based techniques and availability of mutant animal models have enhanced our understanding of the complexities of their regulation and the effect they have on protein function. However, the role that PTMs have in a pathological context still remains unknown for the most part. PTMs enable the modulation of nuclear receptor function in a rapid and reversible manner in response to varied stimuli, thereby dramatically altering their activity in some cases. This review focuses on acetylation, phosphorylation, SUMOylation, and O-GlcNAcylation, which are the 4 most studied PTMs affecting lipid-regulated nuclear receptor biology, as well as on the implications of such modifications on metabolic pathways under homeostatic and pathological situations. Moreover, we review recent studies on the modulation of PTMs as therapeutic targets for metabolic diseases.

Changes in LXRα phosphorylation promote a novel diet-induced transcriptome that alters the transition from fatty liver to steatohepatitis

“…We now propose that changes in LXRα phosphorylation play a crucial role in these transitional stages of the disease. understanding of how these modifications impact on metabolic diseases is scarce (7). Notably, the physiological consequences of LXRα phosphorylation, sumoylation and acetylation have only been studied in vitro or non-specifically in animal models by pharmacologically or genetically altering the enzymes enhancing or inhibiting these modifications (7).…”

“…understanding of how these modifications impact on metabolic diseases is scarce (7). Notably, the physiological consequences of LXRα phosphorylation, sumoylation and acetylation have only been studied in vitro or non-specifically in animal models by pharmacologically or genetically altering the enzymes enhancing or inhibiting these modifications (7). To directly address the impact of LXRα phosphorylation on NAFLD progression, we generated a novel mouse model harbouring an S196A mutation that disrupts LXRα phosphorylation at Ser196.…”

“…In addition, LXRs act as modulators of inflammation and immunity (4) and show anti-inflammatory and anti-fibrotic activities in acute liver disease models (5,6). Besides ligand binding, LXR activity is modulated by post-translational modifications (7). We and others previously showed that LXRα is phosphorylated at Ser196 (Ser198 in the human homolog) (8)(9)(10) and that ligand-induced LXRα phosphorylation at this site alters its activity in a gene-specific manner (8,10).…”

Disrupting myeloid-specific LXRα phosphorylation promotes FoxM1 expression and modulates atherosclerosis by inducing macrophage proliferation

“…Liver X receptors (LXRs) are ligand activated transcription factors that play vital roles in cholesterol homeostasis (3) and inflammation (4). LXRs are expressed as two isotypes; LXRα and LXRβ, which display 78% sequence homology, yet vary in their tissue expression and regulation (5). Both LXRs are endogenously activated by oxidized metabolites of cholesterol (6) and…”

“…LXRα transcriptional activity can be modulated by several posttranslational modifications (5) including phosphorylation at serine (S) 198 in the human sequence, corresponding to S196 in the mouse orthologue. We have demonstrated that modulation of LXRα phosphorylation significantly modifies its target gene repertoire in macrophage cell lines overexpressing the receptor, thereby altering pathways known to be relevant to the development of atherosclerosis (13,14).…”