"Decoding the Role of NCOR1/2 and Glucocorticoid Receptor in Liver Function"
In a groundbreaking study published in Nature Metabolism, a research team led by Mitchell Lazar has unveiled a remarkable discovery about the intricate workings of the liver. The findings shed light on the unexpected and pivotal role played by the coregulators NCOR1 and NCOR2 (collectively known as NCOR1/2) in orchestrating hepatic function, with far-reaching implications for our understanding of metabolic disorders.
Traditionally, NCOR proteins have been associated with their repressive functions within the liver, working in tandem with the chromatin-relaxing enzyme HDAC3 to regulate lipogenic gene programs. However, this new study uncovers a previously unrecognized, HDAC3-independent and gene-activating function of NCOR1/2 that is crucial for glucose homeostasis.
The researchers found that the depletion of NCOR1/2 in adult mouse livers led to a rapid onset of liver failure, marked by splenomegaly, fibrosis, steatosis, and inflammation. Surprisingly, this phenotype was more severe than that observed in single knockouts, suggesting the existence of previously unidentified transcriptional targets of NCOR1/2.
Through RNA sequencing, the team uncovered a vital role for NCOR1/2 in activating genes essential for glucose regulation, a finding that was corroborated by the severe hypoglycemia exhibited by NCOR1/2 double-knockout mice during fasting. Mechanistically, the researchers discovered that NCOR1/2 coordinate the regulation of chromatin accessibility, particularly at enhancer sites associated with gluconeogenesis, and are essential for the binding of the glucocorticoid receptor (GR) to the chromatin of glucoregulatory genes.
This remarkable discovery challenges the long-held perception of NCOR proteins as solely repressive regulators and highlights their unexpected ability to activate gene expression programs crucial for metabolic homeostasis. The findings have far-reaching implications, not only for our understanding of the complex interplay between coregulators and nuclear receptors in liver function but also for potential therapeutic avenues.
The researchers envision that this newfound understanding of the pivotal role of NCOR1/2 in regulating the fasting response could help address the undesirable hyperglycemic side effects often associated with pharmacological glucocorticoid therapy. By selectively targeting the NCOR1/2-mediated activation of gluconeogenesis, future approaches may be able to alleviate these detrimental effects and improve the management of chronic inflammatory conditions requiring long-term glucocorticoid treatment.
As the field of coregulator research continues to evolve, this study by Hauck and colleagues serves as a powerful reminder of the versatility and importance of these transcriptional modulators in orchestrating metabolic pathways. The insights gained from this work open up new avenues for exploring the potential involvement of aberrant NCOR1/2 expression in human liver pathologies, such as metabolic dysfunction-associated steatotic liver disease (MASLD) and glucose dysregulation disorders. With these findings, the stage is set for further advancements in our understanding of the intricate mechanisms governing liver function and the development of innovative therapeutic strategies targeting coregulator-mediated pathways.
Source: https://www.nature.com/articles/s42255-024-01028-5
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