Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Department of Pharmacology, The Traditional Chinese Medicine Hospital of Huoshan County, Luan 237200, Anhui, China.
Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China.
Biochem Pharmacol. 2024 Jul;225:116334. doi: 10.1016/j.bcp.2024.116334. Epub 2024 May 31.
Alcoholic liver injury (ALI) stands as a prevalent affliction within the spectrum of complex liver diseases. Prolonged and excessive alcohol consumption can pave the way for liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Recent findings have unveiled the protective role of proline serine-threonine phosphatase interacting protein 2 (PSTPIP2) in combating liver ailments. However, the role of PSTPIP2 in ALI remains mostly unknown. This study aimed to determine the expression profile of PSTPIP2 in ALI and to uncover the mechanism through which PSTPIP2 affects the survival and apoptosis of hepatocytes in ALI, using both ethyl alcohol (EtOH)-fed mice and an EtOH-induced AML-12 cell model. We observed a consistent decrease in PSTPIP2 expression both in vivo and in vitro. Functionally, we assessed the impact of PSTPIP2 overexpression on ALI by administering adeno-associated virus 9 (AAV9)-PSTPIP2 into mice. The results demonstrated that augmenting PSTPIP2 expression significantly shielded against liver parenchymal distortion and curbed caspase-dependent hepatocyte apoptosis in EtOH-induced ALI mice. Furthermore, enforcing PSTPIP2 expression reduced hepatocyte apoptosis in a stable PSTPIP2-overexpressing AML-12 cell line established through lentivirus-PSTPIP2 transfection in vitro. Mechanistically, this study also identified signal transducer and activator of transcription 3 (STAT3) as a direct signaling pathway regulated by PSTPIP2 in ALI. In conclusion, our findings provide compelling evidence that PSTPIP2 has a regulatory role in hepatocyte apoptosis via the STAT3 pathway in ALI, suggesting PSTPIP2 as a promising therapeutic target for ALI.
酒精性肝损伤（ALI）是一种常见的复杂肝脏疾病。长期和过量饮酒会导致肝纤维化、肝硬化，甚至肝细胞癌。最近的研究结果揭示了脯氨酸-丝氨酸-苏氨酸磷酸酶相互作用蛋白 2（PSTPIP2）在对抗肝脏疾病方面的保护作用。然而，PSTPIP2 在 ALI 中的作用仍知之甚少。本研究旨在确定 PSTPIP2 在 ALI 中的表达谱，并通过使用乙醇（EtOH）喂养的小鼠和 EtOH 诱导的 AML-12 细胞模型，揭示 PSTPIP2 影响 ALI 中肝细胞存活和凋亡的机制。我们观察到 PSTPIP2 的表达在体内和体外均一致下降。功能上，我们通过向小鼠注射腺相关病毒 9（AAV9）-PSTPIP2 来评估 PSTPIP2 过表达对 ALI 的影响。结果表明，增强 PSTPIP2 的表达可显著防止肝实质变形，并抑制 EtOH 诱导的 ALI 小鼠中依赖半胱天冬酶的肝细胞凋亡。此外，通过慢病毒-PSTPIP2 转染在体外建立稳定的 PSTPIP2 过表达 AML-12 细胞系，增强 PSTPIP2 的表达可减少肝细胞凋亡。从机制上讲，这项研究还确定了信号转导和转录激活因子 3（STAT3）是 PSTPIP2 在 ALI 中调节的直接信号通路。总之，我们的研究结果提供了有力的证据，表明 PSTPIP2 通过 STAT3 通路在 ALI 中对肝细胞凋亡具有调节作用，这表明 PSTPIP2 是治疗 ALI 的有希望的靶点。
