Effect of human ether-α-go-go related gene channels on hepatic endoplasmic reticulum stress and apoptosis

doi:10.3969/j.issn.1006-7795.2019.01.009

Abstract

Abstract: Objective To study the relationship between human ether-α-go-go related gene (hERG) potassium channel and endoplasmic reticulum stress and apoptosis in hepatocytes. Methods The body weight and food intake of male 20-week-old hERG knockout (KO) and wild type (WT) mice, and HE staining of liver paraffin sections was performed. Western blotting was used to detect key enzymes of gluconeogenesis including glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (PEPCK). Western blotting and real-time qPCR methods were used to detect liver apoptosis related genes including cleaved-cysteine aspartyl protease 3 (cleaved-caspase 3), B-cell lymphoma 2 (Bcl2) and Bcl2 associated X protein (Bax). Liver endoplasmic reticulum stress related genes including, phosphorylated-eukaryotic translation initiation factor 2α(p-eIF2α), activating transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP) were also detected. hERG lentivirus was injected via tail vein of KO mice, and Western blotting was used to detect the protein levels of islet and liver endoplasmic reticulum stress and apoptosis related indicators. Results Compared with WT mice, no statistically significant differences was observed in body weight and food intake in KO mice. G6Pase expression level has no significant change, while the up-regulation of PEPCK expression suggested that hERG knockout caused abnormal liver glucose metabolism. The endoplasmic reticulum stress and apoptosis related genes were up-regulated suggesting the presence of endoplasmic reticulum stress and apoptosis in KO mice. After the overexpression of hERG in KO mice, the liver endoplasmic reticulum stress and apoptosis were improved. Conclusion hERG potassium channel can improve glucose metabolism in liver cells with reducing liver endoplasmic reticulum stress and apoptosis.

Key words: human ether-α-go-go related gene, endoplasmic reticulum stress, apoptosis, liver

CLC Number:

Lu Jing, Shen Han, Cheng Cheng, Liu Jingyi, Zhu Xiaorong, Xie Rongrong, Yuan Mingxia, Yang Jinkui. Effect of human ether-α-go-go related gene channels on hepatic endoplasmic reticulum stress and apoptosis[J]. Journal of Capital Medical University, 2019, 40(1): 45-52.

0
/ / Recommend

Add to citation manager EndNote|Reference Manager|ProCite|BibTeX|RefWorks

URL: https://journal03.magtech.org.cn/Jweb_sdykdxxb/EN/10.3969/j.issn.1006-7795.2019.01.009

https://journal03.magtech.org.cn/Jweb_sdykdxxb/EN/Y2019/V40/I1/45

References

[1] Iurlaro R, Muñoz-Pinedo C. Cell death induced by endoplasmic reticulum stress[J]. FEBS J,2015, 283(14):2640-2652.
[2] Hotamisligil G S. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease[J]. Cell,2010, 140(6):900-917.
[3] Hetz C, Chevet E, Harding H P. Targeting the unfolded protein response in disease[J]. Nat Rev Drug Discov,2013, 12(9):703-719.
[4] Biden T J, Boslem E, Chu K Y, et al. Lipotoxic endoplasmic reticulum stress, β cell failure, and type 2 diabetes mellitus[J]. Trends Endocrinol Metab,2014, 25(8):389-398.
[5] Tan Y, Dourdin N, Wu C, et al. Ubiquitous calpains promote caspase-12 and JNK activation during endoplasmic reticulum stress-induced apoptosis[J]. J Biol Chem,2006, 281(23):16016-16024.
[6] Nagy G, Szarka A, Lotz G, et al. BGP-15 inhibits caspase-independent programmed cell death in acetaminophen-induced liver injury[J]. Toxicol Appl Pharmacol,2010, 243(1):96-103.
[7] Ashcroft F M, Rorsman P. ATP-sensitive K⁺ channels:a link between B-cell metabolism and insulin secretion[J]. Biochem Soc Trans,1990, 18(1):109-111.
[8] Vandenberg J I, Perry M D, Perrin M J, et al. hERG K(+) channels:structure, function, and clinical significance[J]. Physiol Rev,2012, 92(3):1393-1478.
[9] Mühlbauer E, Bazwinsky I, Wolgast S, et al. Circadian changes of ether-a-go-go-related-gene (Erg) potassium channel transcripts in the rat pancreas and β-cell[J]. Cell Mol Life Sci,2007, 64(6):768-780.
[10] Babcock J J, Li M. hERG channel function:beyond long QT[J]. Acta Pharmacol Sin,2013, 34(3):329-335.
[11] Hyltén-Cavallius L, Iepsen E W, Albrechtsen N J, et al. Patients with long-QT syndrome caused by impairedhERG-encoded Kv11.1 potassium channel have exaggerated endocrine pancreatic and incretin function associated with reactive hypoglycemia[J]. Circulation,2017, 135(18):1705-1719.
[12] Rosati B, Marchetti P, Crociani O, et al. Glucose-and arginine-induced insulin secretion by human pancreatic beta-cells:the role of HERG K(+) channels in firing and release[J]. FASEB J,2000, 14(15):2601-2601.
[13] Qiu H Y, Yuan S S, Yang F Y, et al. HERG protein plays a role in moxifloxacin-induced hypoglycemia[J]. J Diabetes Res,2016,2016:6741745.
[14] Ruiz-Vela A, Opferman J T, Cheng H Y, et al. Proapoptotic BAX and BAK control multiple initiator caspases[J]. EMBO Rep,2005, 6(4):379-385.
[15] Mithieux G. New knowledge regarding glucose-6 phosphatase gene and protein and their roles in the regulation of glucose metabolism[J]. Eur J Endocrinol,1997, 136(2):137-145.
[16] Kim S Y, Cho B H, Kim U H. CD38-mediated Ca²⁺ signaling contributes to angiotensin Ⅱ-induced activation of hepatic stellate cells:Attenuation of hepatic fibrosis by CD38 ablation[J]. J Biol Chem,2010, 285(1):576-582.