A team led by Professor Eckardt Treuter at the Karolinska Institutet has investigated the molecular mechanisms of how the nuclear lipid receptors LRH-1 and LXR inhibit inflammatory gene expression in liver during the so-called ‘acute phase response’.
The study identified GPS2, a protein that directly interacts with receptors, as a central component of a sophisticated protein network – or ‘genomic positioning system’ – determining where and when these lipid receptors can function anti-inflammatory.
The identified pathway connects metabolism and inflammation and, therefore, is relevant for the understanding of metabolic diseases, such as diabetes and atherosclerosis. The researchers suspect even broader roles of related pathways in different tissues linked to metabolic diseases and to cancers.
‘We are now closer to understanding, at the molecular level, how dysregulation of individual components of these pathways causes alterations in gene expression that contribute to the development of metabolic diseases linked to inflammation,’ states Professor Treuter. ‘This knowledge may open up novel pharmacological interventions. For example, drugs that stabilize receptor interactions with GPS2 could possibly trigger the anti-inflammatory pathway.’
Nuclear receptors are regulatory proteins within the cell nucleus that can bind directly to a variety of hormones, metabolites and pharmaceuticals. Binding affects the activity of these proteins, causing them to switch genes on or off, which, in turn, leads to increased or decreased production of the proteins that carry out diverse functions within the cell.
Numerous nuclear receptors are known as master regulators of lipid metabolism and homeostasis. Latest research indicates that these receptors also have important roles in the control of inflammation via mechanisms that have yet to be clarified.
Further reading
Venteclef, N. et al. (2010) GPS2-dependent corepressor/SUMO pathways govern anti-inflammatory actions of LRH-1 and LXRb in the hepatic acute phase response. Genes & Development 24, 381–395