Protein kinase R and the metabolic syndrome

Abstract

Metabolic syndrome greatly increases the risk for developing metabolic and cardiovascular disorders and has reached epidemic proportions globally. Despite recent advances in medical science, scientific understandings on the root mechanisms of metabolic syndrome are still not fully understood, and such insufficient knowledge contributes to the relative lack of effective treatments for such diseases. Protein Kinase R (PKR) is a serine threonine kinase activated during various stress conditions. Activation of PKR can increase reactive oxygen product generation, cause oxidative stress and inflammation. In this review we discuss the potential role of PKR in metabolic syndrome, pathways activated by it and the interrelationship between pathways activated, modes of propagation if one of the pathways is inhibited or activated. Specific and effective inhibitors of PKR are being developed and can become potential treatment for metabolic syndrome and prevent many diseases.

Double‐stranded RNA‐dependent protein kinase signalling and paradigms of cardiometabolic syndrome

“…Besides dsRNA, endoplasmic reticulum (ER) stress, mechanical stress, high‐fat diet, pathogens, environmental stress, haeme limitation, cytokines (TNF‐α, IL‐1β) and irradiation also possess the ability to activate PKR . In addition, researchers have found that the PACT is a plausible cellular activator of PKR which can cause the PKR phosphorylation , while others have demonstrated that protein kinase R (PKR)‐associated protein X (RAX), murine counterpart for PACT , is accountable for the activation of PKR at cellular level, when stimulated by any extracellular stress stimuli .…”

“…Upon activation, PKR phosphorylates several downstream substrates such as protein phosphatase 2A (PP2A) and eukaryotic translation initiation factor eIF‐2α that are involved in modulating protein synthesis . Notably, PKR is implicated in regulating various physiological and pathological functions such as cell growth, apoptosis, stress, transcription and many types of malignancies .…”

“…Remarkably, oxidative stress and activated PKR are the most prominent risk factors involved in the progression and development of numerous diseases, ranging from the neurodegenerative disorders such as Alzheimer's disease to a broad array of interconnected metabolic diseases including several forms of malignancies . Studies by Bahal et al and Udumula et al have illustrated the role of PKR in metabolic diseases . PKR is activated by multiple stimuli which may be either internal or external such as ER stress, nutrient excess and many other factors .…”

“…It is clear from the above facts that PKR is emerging as a newer perspective involved in the development and progression of several metabolic diseases such as diabetes and obesity . However, recently it has been hypothesized that PKR is also implicated in the development of hypertension and diabetic cardiomyopathy .…”