Abstract
Proper coordination of cellular metabolism and its integration with immune response is paramount to function of cells, organs, and organisms. The endoplasmic reticulum is the main site for protein and lipid synthesis, trafficking, and the storage of cellular calcium. ER also plays a significant role in adaptation to metabolic fluctuations, adaptation to metabolic challenges and their integration to immune response. This important integrated response is disrupted by metabolic stress of chronic metabolic diseases such as obesity and diabetes in animal models and humans. Restoration of the ER adaptive folding responses by genetic or chemical means improve metabolic homeostasis in preclinical models and humans. Therefore, understanding the compositional, structural, and functional regulation of the ER and the mechanisms giving rise to its dysfunction remain as critical areas of investigation and carry important translational opportunities. In recent studies, we discovered interactions between inflammatory signalling pathways and the adaptive responses that emanate from the ER during metabolic stress and pathological interactions between the endoplasmic reticulum and mitochondria that disrupt calcium homeostasis and the function of these organelles. Here, I will present emerging evidence integrating metaflammation to endoplasmic reticulum and mitochondria function and the role of ER during metabolic adaptations. I will also present our most recent observations on a novel pathway mediated by an ER bound transcription factor, which orchestrates previously unknown countermeasures against lipotoxicity in the liver. Finally, how these molecular mechanisms may be exploited to understand chronic inflammatory diseases and leveraged to design novel and effective preventive and therapeutic strategies will be discussed.