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LXRα Phosphorylation in Cardiometabolic Disease: Insight From Mouse Models
Maud Voisin1, Matthew C Gage2, Natalia Becares3
1Department of Microbiology, New York University School of Medicine, New York, New York, US.
Abstract:
Posttranslational modifications, such as phosphorylation, are a powerful means by which the activity and function of nuclear receptors such as LXRα can be altered. However, despite the established importance of nuclear receptors in maintaining metabolic homeostasis, our understanding of how phosphorylation affects metabolic diseases is limited. The physiological consequences of LXRα phosphorylation have, until recently, been studied only in vitro or nonspecifically in animal models by pharmacologically or genetically altering the enzymes enhancing or inhibiting these modifications. Here we review recent reports on the physiological consequences of modifying LXRα phosphorylation at serine 196 (S196) in cardiometabolic disease, including nonalcoholic fatty liver disease, atherosclerosis, and obesity. A unifying theme from these studies is that LXRα S196 phosphorylation rewires the LXR-modulated transcriptome, which in turn alters physiological response to environmental signals, and that this is largely distinct from the LXR-ligand-dependent action.
Insights
Phosphorylation of liver X receptor alpha (LXRα) at serine 196 (S196) significantly impacts metabolic diseases. This modification rewires the LXRα transcriptome, altering physiological responses independently of LXRα ligand action.
Area of Science:
- Metabolic Regulation
- Molecular Endocrinology
- Nuclear Receptor Signaling
Background:
- Nuclear receptors, including liver X receptor alpha (LXRα), are crucial for metabolic homeostasis.
- Posttranslational modifications like phosphorylation can modulate LXRα activity, but their role in metabolic diseases remains unclear.
- Previous studies on LXRα phosphorylation effects were limited to in vitro or nonspecific in vivo models.
Purpose of the Study:
- To review recent findings on the physiological impact of LXRα phosphorylation at serine 196 (S196) in cardiometabolic diseases.
- To elucidate how LXRα S196 phosphorylation influences conditions such as nonalcoholic fatty liver disease, atherosclerosis, and obesity.
- To differentiate the effects of LXRα S196 phosphorylation from canonical LXRα ligand-dependent actions.
Main Methods:
- Review of recent scientific literature focusing on LXRα phosphorylation at S196.
- Analysis of studies investigating the physiological consequences in animal models and relevant disease contexts.
- Examination of transcriptomic and physiological data related to LXRα S196 modification.
Main Results:
- LXRα phosphorylation at S196 significantly alters the LXRα-modulated transcriptome.
- This phosphorylation event rewires cellular responses to environmental cues.
- The physiological effects of LXRα S196 phosphorylation are largely independent of LXRα ligand binding.
Conclusions:
- LXRα S196 phosphorylation represents a critical regulatory mechanism in cardiometabolic health.
- Modulating LXRα phosphorylation offers a distinct therapeutic avenue for metabolic diseases, separate from traditional LXRα agonism.
- Understanding LXRα S196 phosphorylation is key to unraveling complex metabolic disease pathophysiology.
