Nuclear Receptors and Lipid Sensing

Fluctuations in concentration of diverse lipid classes occur in response to diet and metabolism. These changes are managed and mediated by a cell network of enzymes, pumps, and carriers under the control of the lipid responsive nuclear receptors. The understanding of how dysregulation of lipid metabolism are causes and indicators of disease beyond the cardiovascular system has developed in the last decade. A particular emphasis on the role of lipids and lipid-sensing nuclear receptors has emerged in the fields of cancer and the immune system’s interaction with cancer. The range of known lipid-based ligands has also expanded. Lipids are not just signalling molecules, but also play structural roles in cells and tissues, for example as major constituents of the lipid bilayer – positioning them as integrators and mediators of signaling. This chapter will discuss the major groups of lipid-sensing nuclear receptors focusing on the liver x receptors, farnesoid x receptor, and the peroxisome proliferator-activated receptors. Initially the reader is presented with information on how these receptors behave and function at the molecular biology level, the range of selective modulation of function by endogenous ligands, and examples of how activity is fine-tuned by mechanisms such as miRNA regulation and post-translational modification of the proteins. We then explore the advances in understanding that have positioned these receptors as therapeutic targets in cancer and immuno-oncology. Finally, the chapter explains the gaps in understanding and experimental challenges that should be prioritized in the coming decade.