Alpha lipoic acid attenuates ER stress and improves glucose uptake through DNAJB3 cochaperone

Abstract

Persistent ER stress, mitochondrial dysfunction and failure of the heat shock response (HSR) are fundamental hallmarks of insulin resistance (IR); one of the early core metabolic aberrations that leads to type 2 diabetes (T2D). The antioxidant α-lipoic acid (ALA) has been shown to attenuate metabolic stress and improve insulin sensitivity in part through activation of the heat shock response (HSR). However, these studies have been focused on a subset of heat shock proteins (HSPs). In the current investigation, we assessed whether ALA has an effect on modulating the expression of DNAJB3/HSP40 cochaperone; a potential therapeutic target with a novel role in mitigating metabolic stress and promoting insulin signaling. Treatment of C2C12 cells with 0.3 mM of ALA triggers a significant increase in the expression of DNAJB3 mRNA and protein. A similar increase in DNAJB3 mRNA was also observed in HepG2 cells. We next investigated the significance of such activation on endoplasmic reticulum (ER) stress and glucose uptake. ALA pre-treatment significantly reduced the expression of ER stress markers namely, GRP78, XBP1, sXBP1 and ATF4 in response to tunicamycin. In functional assays, ALA treatment abrogated significantly the tunicamycin-mediated transcriptional activation of ATF6 while it enhanced the insulin-stimulated glucose uptake and Glut4 translocation. Silencing the expression of DNAJB3 but not HSP72 abolished the protective effect of ALA on tunicamycin-induced ER stress, suggesting thus that DNAJB3 is a key mediator of ALA-alleviated tunicamycin-induced ER stress. Furthermore, the effect of ALA on insulin-stimulated glucose uptake is significantly reduced in C2C12 and HepG2 cells transfected with DNAJB3 siRNA. In summary, our results are supportive of an essential role of DNAJB3 as a molecular target through which ALA alleviates ER stress and improves glucose uptake.

Oxoplatin‐Based Pt(IV) Lipoate Complexes and Their Biological Activity

“…[2 -5] Besides the regulation of the redox status in cells through thiol/disulfide exchange reactions, [3,6,7] ALA acts as an essential cofactor for α-ketoacid dehydrogenase complexes (e. g., pyruvate dehydrogenase, PDH) in the cellular energy metabolism. [8,9] The activity of PDH, which catalyzes the oxidative carboxylation of pyruvate in the mitochondria and thereby bridges the anaerobic and aerobic metabolism, [9,10] can be enhanced by ALA supplementation. [11] The previous mentioned characteristics of ALA contribute to the reported inhibition of proliferation in various cancer cell lines, which feature inefficient aerobic glycolysis ('Warburg effect') and oxidative stress.…”

“…α‐Lipoic acid (ALA), first isolated and characterized by Lester Reed and coworkers in 1951, [1] has been extensively studied for pharmaceutical and nutraceutical potentials regarding its antioxidant and anti‐inflammatory properties [2–5] . Besides the regulation of the redox status in cells through thiol/disulfide exchange reactions, [3,6,7] ALA acts as an essential cofactor for α‐ketoacid dehydrogenase complexes (e. g., pyruvate dehydrogenase, PDH) in the cellular energy metabolism [8,9] . The activity of PDH, which catalyzes the oxidative carboxylation of pyruvate in the mitochondria and thereby bridges the anaerobic and aerobic metabolism, [9,10] can be enhanced by ALA supplementation [11] .…”

The complex metabolic interactions of liver tissue and hepatic exosome in PCOS mice at young and middle age

“…On the other hand, the glutathione (GSH) was significantly increased in MP exosomes. GSH is an antioxidant involved in protecting cells from oxidative damage, and it has been reported that oxidative stress is a key mechanism of developing IR ( Diane et al, 2020 ) and the pathophysiology of PCOS. Thus, we speculated that compared to YP groups, the increased age imposed greater stress on MP liver, leading to the level increase of GSH, thereby providing increased antioxidant defense to protect themselves from toxic reactive oxygen species (ROS) ( Mohamed et al, 2020 ).…”

Alpha-Lipoic Acid and Glucose Metabolism: A Comprehensive Update on Biochemical and Therapeutic Features

“…Moreover, within the cell ALA could carry out additional functions associated with glucose metabolism; in particular, it could influence mitochondrial biogenesis and endoplasmic reticulum (ER) activity. In fact, ALA stimulates the expression of mitochondrial markers such as TFAM, PPARɣ and PGC1α in C2C12 cells (a myoblast cell line) and the expression of gene encoding for representative antioxidant enzymes such as glutathione peroxidase (GPX1) and superoxide dismutase 1 (SOD1) [ 40 ]. In glucose-treated rats, the decrease in PPARγ protein levels caused by oxidative stress is prevented or attenuated if they are fed with ALA [ 41 ].…”

“…However, to date, the contribution of ALA-induced PPARγ expression to insulin sensitivity cannot be clearly quantified. In the endoplasmic reticulum, ALA increases the endogenous expression of DNAJB3 cochaperone, heat shock proteins (HSP25 and HSP27) in C2C12 cells [ 40 , 42 ]. DNAJB3 cochaperone has been associated with reduced metabolic stress, improved insulin signalling and glucose uptake in previous in vitro and in vivo studies (3T3-L1 adipocytes and human obese subjects) [ 43 , 44 ].…”