Endogenous Pathogenic dsRNA Pathways

With the rise of obesity, the prevalence of metabolic diseases such as insulin resistance and type 2 diabetes (T2D) has increased to pandemic proportions. During the pathogenesis of obesity, a broad array of inflammatory and stress responses are frequently evoked in insulin-targeted metabolic tissues such as liver and adipose tissue, leading to chronic, low grade, and local inflammation. This atypical state plays a central role in the disruption of systemic metabolic homeostasis. However, the molecular basis for the induction of metabolically-driven anomalous inflammatory and stress responses and their associated pathophysiological responses remains elusive. Modulation of pathways that initiate the inflammation and cause dysregulated metabolic homeostasis has become a key therapeutic possibility.

We have hypothesized that changes in RNA networks are provoked in an obese condition and these changes are recognized by inflammatory RNA-binding proteins, leading to the anomalous inflammatory and stress responses. This hypothesis is based on our previous findings. Namely, double-stranded RNA (dsRNA)-dependent kinase (PKR), a pro-inflammatory stress kinase, is activated in metabolically-driven stress conditions, such as obesity and palmitate exposure, and this activation requires PKR’s dsRNA-binding activity. These findings indicate that endogenous dsRNAs are sensed by PKR and activate it in the stress conditions. Recently, we have further demonstrated that trans-activation response-RNA binding protein (TRBP), which is also a dsRNA-binding protein, is an upstream molecule of the dsRNA-PKR activated complex and is required for PKR activation in the stress conditions. In obese mouse liver, inactivation of TRBP results in reversal of hepatic inflammatory responses including activation of PKR and c-Jun N-terminal kinase (JNK), accompanied by improved hepatic steatosis and systemic glucose intolerance. These findings led us to hypothesize that TRBP could be the signaling node that senses metabolic stress levels through the recognition of altered dsRNA networks, and link to PKR-mediated inflammatory signaling pathway.