Abstract: Disulfide-bond A oxidoreductase-like protein (DsbA-L) is a molecular chaperone involved in the multimerization of adiponectin. Recent studies have found that DsbA-L is related to metabolic diseases including gestational diabetes mellitus (GDM), and can be regulated by peroxisome proliferator-activated receptor γ (PPARγ) agonists; the specific mechanism, however, is uncertain. Furthermore, the relationship between DsbA-L and the novel adipokine chemerin is also unclear. This article aims to investigate the role of DsbA-L in the improvement of insulin resistance by PPARγ agonists in trophoblast cells cultured by the high-glucose simulation of GDM placenta. Immunohistochemistry and western blot were used to detect differences between GDM patients and normal pregnant women in DsbA-L expression in the adipose tissue. The western blot technique was performed to verify the relationship between PPARγ agonists and DsbA-L, and to explore changes in key molecules of the insulin signaling pathway, as well as the effect of chemerin on DsbA-L. Results showed that DsbA-L was significantly downregulated in the adipose tissue of GDM patients. Both PPARγ agonists and chemerin could upregulate the level of DsbA-L. Silencing DsbA-L affected the function of rosiglitazone to promote the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (PKB)/AKT pathway. Therefore, it is plausible to speculate that DsbA-L is essential in the environment of PPARγ agonists for raising insulin sensitivity. Overall, we further clarified the mechanism by which PPARγ agonists improve insulin resistance.

高糖细胞模型中DsbA-L基因沉默损害PPARγ激动剂改善胰岛素抵抗的功能

[1]Achari AE, Jain SK, 2017. Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction. Int J Mol Sci, 18(6):1321.

[2]Arkun Y, 2016. Dynamic modeling and analysis of the cross-talk between insulin/AKT and MAPK/ERK signaling pathways. PLoS ONE, 11(3):e0149684.

[3]Bai JL, Cervantes C, Liu J, et al., 2017. DsbA-L prevents obesity-induced inflammation and insulin resistance by suppressing the mtDNA release-activated cGAS-cGAMP-STING pathway. Proc Natl Acad Sci USA, 114(46):12196-12201.

[4]Basak S, Das MK, Srinivas V, et al., 2015. The interplay between glucose and fatty acids on tube formation and fatty acid uptake in the first trimester trophoblast cells, HTR8/SVneo. Mol Cell Biochem, 401(1-2):11-19.

[5]Chen HZ, Bai JL, Dong F, et al., 2017. Hepatic DsbA-L protects mice from diet-induced hepatosteatosis and insulin resistance. FASEB J, 31(6):2314-2326.

[6]Deng X, Yang G, Zheng X, et al., 2020. Plasma mtDNA copy numbers are associated with GSTK1 expression and inflammation in type 2 diabetes. Diabet Med, 37(11):1874-1878.

[7]Ferland DJ, Garver H, Contreras GA, et al., 2020. Chemerin contributes to in vivo adipogenesis in a location-specific manner. PLoS ONE, 15(2):e0229251.

[8]Gao F, Fang QC, Zhang R, et al., 2009. Polymorphism of DsbA-L gene associates with insulin secretion and body fat distribution in Chinese population. Endocr J, 56(3):487-494.

[9]Giannakou K, Evangelou E, Yiallouros P, et al., 2019. Risk factors for gestational diabetes: an umbrella review of meta-analyses of observational studies. PLoS ONE, 14(4):e0215372.

[10]Goralski KB, McCarthy TC, Hanniman EA, et al., 2007. Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism. J Biol Chem, 282(38):28175-28188.

[11]Griffith RJ, Alsweiler J, Moore AE, et al., 2020. Interventions to prevent women from developing gestational diabetes mellitus: an overview of Cochrane Reviews. Cochrane Database Syst Rev, 6(6):CD012394.

[12]He YD, Lu LF, Wei X, et al., 2016. The multimerization and secretion of adiponectin are regulated by TNF-alpha. Endocrine, 51(3):456-468.

[13]Helfer G, Wu QF, 2018. Chemerin: a multifaceted adipokine involved in metabolic disorders. J Endocrinol, 238(2):R79-R94.

[14]Jin D, Sun J, Huang J, et al., 2015. Peroxisome proliferator-activated receptor γ enhances adiponectin secretion via up-regulating DsbA-L expression. Mol Cell Endocrinol, 411:97-104.

[15]Kim SY, England L, Wilson HG, et al., 2010. Percentage of gestational diabetes mellitus attributable to overweight and obesity. Am J Public Health, 100(6):1047-1052.

[16]Kuricova K, Pácal L, Šoupal J, et al., 2016. Effect of glucose variability on pathways associated with glucotoxicity in diabetes: evaluation of a novel in vitro experimental approach. Diabetes Res Clin Pract, 114:1-8.

[17]Lampropoulou E, Lymperopoulou A, Charonis A, 2016. Reduced expression of ERp46 under diabetic conditions in β-cells and the effect of liraglutide. Metabolism, 65(1):7-15.

[18]Lebovitz HE, 2019. Thiazolidinediones: the forgotten diabetes medications. Curr Diab Rep, 19(12):151.

[19]Li ZY, Cheng YJ, Wang DY, et al., 2020. Incidence rate of type 2 diabetes mellitus after gestational diabetes mellitus: a systematic review and meta-analysis of 170,139 women. J Diabetes Res, 2020:3076463.

[20]Liu ML, Liu F, 2012. Up- and down-regulation of adiponectin expression and multimerization: mechanisms and therapeutic implication. Biochimie, 94(10):2126-2130.

[21]Liu ML, Zhou LJ, Xu AM, et al., 2008. A disulfide-bond A oxidoreductase-like protein (DsbA-L) regulates adiponectin multimerization. Proc Natl Acad Sci USA, 105(47):18302-18307.

[22]Liu ML, Xiang RH, Wilk SA, et al., 2012. Fat-specific DsbA-L overexpression promotes adiponectin multimerization and protects mice from diet-induced obesity and insulin resistance. Diabetes, 61(11):2776-2786.

[23]Liu ML, Chen HZ, Wei L, et al., 2015. Endoplasmic reticulum (ER) localization is critical for DsbA-L protein to suppress ER stress and adiponectin down-regulation in adipocytes. J Biol Chem, 290(16):10143-10148.

[24]Lorenzo-Almorós A, Hang T, Peiró C, et al., 2019. Predictive and diagnostic biomarkers for gestational diabetes and its associated metabolic and cardiovascular diseases. Cardiovasc Diabetol, 18:140.

[25]Pal S, Rao GN, Pal A, 2020. High glucose-induced ROS accumulation is a critical regulator of ERK1/2-Akt-tuberin-mTOR signalling in RGC-5 cells. Life Sci, 256:117914.

[26]Plows JF, Stanley JL, Baker PN, et al., 2018. The pathophysiology of gestational diabetes mellitus. Int J Mol Sci, 19(11):3342.

[27]Simpson F, Whitehead JP, 2010. Adiponectin—it’s all about the modifications. Int J Biochem Cell Biol, 42(6):785-788.

[28]Taniguchi CM, Emanuelli B, Kahn CR, 2006. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol, 7(2):85-96.

[29]Wang XY, Pan JY, Liu H, et al., 2019. AIM2 gene silencing attenuates diabetic cardiomyopathy in type 2 diabetic rat model. Life Sci, 221:249-258.

[30]Wang ZV, Scherer PE, 2008. DsbA-L is a versatile player in adiponectin secretion. Proc Natl Acad Sci USA, 105(47):18077-18078.

[31]Zhou LJ, Liu ML, Zhang JJ, et al., 2010. DsbA-L alleviates endoplasmic reticulum stress-induced adiponectin downregulation. Diabetes, 59(11):2809-2816.

[32]Zhou X, Wei LJ, Li JQ, et al., 2020. The activation of peroxisome proliferator-activated receptor γ enhances insulin signaling pathways via up-regulating chemerin expression in high glucose treated HTR-8/SVneo cells. Matern-Fetal Med, 2(3):131-140.