Dataset Information

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 ?-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.

SUBMITTER: Diane A

PROVIDER: S-EPMC7687893 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Diane Abdoulaye A Mahmoud Naela N Bensmail Ilham I Khattab Namat N Abunada Hanan A HA Dehbi Mohammed M

Scientific reports 20201124 1

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 ...[more]

PMID: 33235302

Similar Datasets

Project description:The aim of this study was to evaluate the probable protective effect of α-lipoic acid against testicular toxicity in rats exposed to carbimazole during the embryonic period. Time-mated pregnant rats were exposed to carbimazole from the embryonic days 9-21. After completion of the gestation period, all the rats were allowed to deliver pups and weaned. At postnatal day 100, F1 male pups were assessed for the selected reproductive endpoints. Gestational exposure to carbimazole decreased the reproductive organ indices, testicular daily sperm count, epididymal sperm variables viz., sperm count, viable sperm, motile sperm and HOS-tail coiled sperms. Significant decrease in the activity levels of 3β- and 17β-hydroxysteroid dehydrogenases and expression of StAR mRNA levels with a significant increase in the total cholesterol levels were observed in the testis of experimental rats over the controls. These events were also accompanied by a significant reduction in the serum testosterone levels in CBZ exposed rats, indicating reduced steroidogenesis. In addition, the deterioration of the testicular architecture and reduced fertility ability were noticed in the carbimazole exposed rats. Significant reduction in the activity levels of superoxide dismutase, catalase, glutathione reductase, glutathione peroxidase and reduced glutathione content with a significant increase in the levels of lipid peroxidation were observed in the testis of carbimazole exposed rats over the controls. Conversely, supplementation of α-lipoic acid (70 mg/Kg bodyweight) ameliorated the male reproductive health in rats exposed to carbimazole during the embryonic period as evidenced by enhanced reproductive organ weights, selected sperm variables, testicular steroidogenesis, and testicular enzymatic and non-enzymatic antioxidants. To conclude, diminished testicular antioxidant balance associated with reduced spermatogenesis and steroidogenesis might be responsible for the suppressed reproduction in rats exposed to the carbimazole transplacentally. On the other hand, α-lipoic acid through its antioxidant and steroidogenic properties mitigated testicular toxicity which eventually restored the male reproductive health of carbimazole-exposed rats.

Project description:Heat stress accounts for substantial economic loss in the poultry industry by altering the health and performance of chickens. Alpha-lipoic acid (ALA) is a water and fat-soluble antioxidant which is readily absorbed from the intestine resulting in maximum bioavailability. Moreover, ALA acts as a coenzyme in glucose metabolism and helps generate other antioxidants. Considering these benefits, we hypothesized that dietary supplementation of ALA would help mitigate heat stress in poultry. A total of 72 Day-old broiler chicks were randomly assigned into three treatment groups: no heat stress (NHS), heat stress with basal diet (HS), and heat stress with alpha-lipoic acid (HS+ALA); each treatment group had 6 replicate pens with 4 birds in each pen (n = 24/group). The allocated birds were raised under standard husbandry practices for 3 weeks. After 21 d, birds in the HS and HS+ALA groups were exposed to heat stress (33°C for 8 hours during the day) for 3 weeks, while the NHS group was reared under normal conditions (22-24°C). The HS+ALA group received a basal finisher diet fortified with ALA (500 mg/kg) during the treatment period (22 to 42 d), while other birds were provided with the basal finisher diet. Weekly body weight and feed intake were recorded. The cecum digesta for volatile fatty acids (VFAs) analysis and 16S rRNA sequencing for the gut microbiota analysis; and the ileum tissue samples for histological and gene expression analyses were collected on d 42. Exposure to heat stress decreased (P<0.05) average daily gain (ADG) and final body weight (FBW) in the HS group compared to the NHS group, the supplementation of ALA improved (P<0.05) ADG and FBW in heat-stressed birds. Furthermore, birds in the HS+ALA group had increased (P<0.05) expression of HSP90, PRDX1, GPX3, SOD2, OCLN, and MUC2 genes and higher (P<0.05) concentrations of major VFAs (acetate, propionate, and butyrate). The dietary ALA supplementation also improved the villus height and villus height to crypt depth ratio in the HS+ALA group. The microbial diversity analysis revealed significant abundance (P<0.05) of beneficial bacteria Lactobacillus and Peptostreptococcaceae in the cecum of the ALA group. These results indicate that dietary ALA supplementation effectively mitigates the negative effects of heat stress in broilers by improving the expression of heat-shock, tight-junction, antioxidants, and immune-related genes in the intestine, improving villus structures, increasing concentration of major VFAs, and enriching the beneficial microbiota.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets