DNAJB3 as a Novel Target of Alpha-lipoic Acid: Significance for Attenuating Endoplasmic Reticulum Stress

Increased insulin resistance (IR) in peripheral organs is one of the early and primary core metabolic defects in the pathogenesis of obesity and type 2 diabetes (T2D); two metabolic diseases that are spreading at alarming rates worldwide. Understanding the mechanisms of IR and discovering therapeutic targets/pathways to prevent IR and improve insulin sensitivity are imperative to reduce the epidemic spread of obesity and T2D. Metabolic stress is a key hallmark of T2D and it results from the unbalance between stress and anti-stress defense mechanisms, thus leading to a metabolically toxic environment in insulin responsive sites. This results in the activation of several protein kinases that interfere with the insulin signal transduction pathway. The expression of DNAJB3, a member of the HSP40 family, was recently shown to be significantly impaired in obese and T2D patients. Restoring its normal expression was associated with reduced metabolic stress and improved glucose homeostasis both in vivo and in vitro, suggesting DNAJB3 as a potential drug target for the control and management of metabolic defects leading to IR and T2D.The overall objective of this thesis is to identify drugs that induce the expression of DNAJB3 in vitro in C2C12 myoblasts. Accordingly, we found a novel role of -lipoic acid in stimulating the expression of DNAJB3. We further investigated the effect of -lipoic acid on mitigating metabolic stress and if yes, whether DNAJB3 is a mediator for such effect. -Lipoic acid improved mitochondrial function/biogenesis, stimulated the oxidative stress scavenging system and alleviated ER stress. Knocking down the expression of DNAJB3 revealed its role as a molecular intermediate through which -lipoic acid mediates its beneficial effect in reducing ER stress.