Src-mediated Tyr353 phosphorylation of IP3R1 promotes its stability and causes apoptosis in palmitic acid-treated hepatocytes
Src-mediated Tyr353 phosphorylation of IP3R1 promotes its stability and causes apoptosis in palmitic acid-treated hepatocytes
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DOI：
10.1016/j.yexcr.2020.112438
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发表时间：
2021-01-06
影响因子：
3.7
通讯作者：
Chen, Yaxi
中科院分区：
文献类型：
--
作者：
Yu, Ting;Zheng, Enze;Chen, Yaxi
棕榈酸（PA）诱导的肝细胞凋亡是非酒精性脂肪性肝病（NAFLD）进展的关键。肌醇1，4，5-三磷酸受体1（Inositol 1，4，5-trisphosphate receptor type 1，IP 3R 1）是一种细胞内钙释放通道，参与PA诱导的肝细胞凋亡。虽然IP 3R 1的表达在NAFLD患者和PA治疗的肝细胞中升高，但仍不清楚PA如何促进IP 3R 1的表达。本研究结果表明，PA可诱导肝细胞线粒体功能障碍和凋亡，并伴随着IP 3R 1表达的增加。使用siRNA抑制IP 3R 1表达可改善PA诱导的线粒体功能障碍。此外，PA增强了IP 3R 1蛋白的稳定性，而不是增加其mRNA水平。PA还促进了肝细胞中IP 3R 1在Tyr 353位点的磷酸化，并增加了src的磷酸化。src激酶抑制剂（SU 6656）可显著降低IP 3R 1的Tyr 353磷酸化水平，降低其稳定性。此外，SU 6656还改善线粒体功能并减少肝细胞凋亡。结论：PA通过激活src通路促进IP 3R 1的Tyr 353磷酸化，增加IP 3R 1的蛋白稳定性，导致肝细胞线粒体Ca 2+超载和线粒体功能障碍。我们的研究结果还表明，抑制src/IP 3R 1通路，如通过SU 6656，可能是治疗NAFLD的一种新的潜在治疗方法。
Palmitic acid (PA)-induced hepatocyte apoptosis is critical for the progression of nonalcoholic fatty liver disease (NAFLD). Inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) is an intracellular Ca2+-release channel and is involved in PA-induced hepatocyte apoptosis. While the expression of IP3R1 is elevated in patients with NAFLD and in hepatocytes treated with PA, it remains unclear how PA promotes the expression of IP3R1. In present study, our results showed that PA induced mitochondrial dysfunction and apoptosis, which is accompanied with the increase of the IP3R1 expression in hepatic cells. The inhibition of IP3R1 expression using siRNA ameliorated the PA-induced mitochondrial dysfunction. Furthermore, PA enhanced the stability of the IP3R1 protein instead of an increase in its mRNA levels. PA also promoted the phosphorylation of IP3R1 at the Tyr353 site and increased the phosphorylation of src in hepatic cells. Moreover, an inhibitor of src kinase (SU6656) significantly reduced the Tyr353 phosphorylation of IP3R1 and decreased its stability. In addition, SU6656 improved mitochondrial function and reduced apoptosis in hepatocytes. Conclusion: PA promotes the Tyr353 phosphorylation of IP3R1 by activating the src pathway and increasing the protein stability of IP3R1, which consequently results in mitochondrial Ca2+ overload and mitochondrial dysfunction in hepatic cells. Our results also suggested that inhibition of the src/IP3R1 pathway, such as by SU6656, may be a novel potential therapeutic approach for the treatment of NAFLD.