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.

棕榈酸（PA）诱导的肝细胞凋亡对于非酒精性脂肪肝疾病（NAFLD）的进展至关重要。1型肌醇1,4,5-三磷酸受体（IP3R1）是细胞内Ca ²⁺释放通道并参与PA诱导的肝细胞凋亡。虽然NAFLD患者和接受PA治疗的肝细胞中IP3R1的表达升高，但尚不清楚PA如何促进IP3R1的表达。在本研究中，我们的结果表明PA诱导了线粒体功能障碍和细胞凋亡，并伴随着肝细胞IP3R1表达的增加。使用siRNA抑制IP3R1表达可改善PA诱导的线粒体功能障碍。此外，PA增强了IP3R1蛋白的稳定性，而不是其mRNA水平的增加。PA还促进了Tyr353位点IP3R1的磷酸化，并增加了肝细胞中src的磷酸化。此外，src激酶抑制剂（SU6656）显着降低IP3R1的Tyr353磷酸化并降低其稳定性。此外，SU6656改善了线粒体功能并减少了肝细胞的凋亡。结论：PA通过激活src途径并提高IP3R1的蛋白质稳定性来促进IP3R1的Tyr353磷酸化，从而导致肝细胞线粒体Ca ²⁺超载和线粒体功能障碍。我们的结果还表明，抑制src / IP3R1途径（例如通过SU6656）可能是治疗NAFLD的一种新型潜在治疗方法。