Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
Department of Veterinary Microbiology, College of Veterinary Medicine, Chungnam National University, Daejeon 34134, Republic of Korea.
Mol Med Rep. 2018 Apr;17(4):4989-4998. doi: 10.3892/mmr.2018.8505. Epub 2018 Jan 26.
Binge drinking among alcohol consumers is a common occurrence, and may result in the development of numerous diseases, including liver disorders. It has previously been reported that natural killer T (NKT) cells induce alcohol‑associated liver injury by promoting neutrophil infiltration. In the present study, the role of the orphan nuclear receptor small heterodimer partner (SHP), which is encoded by the NR0B2 gene, in acute binge drinking‑induced liver injury was investigated. SHP‑knockout (KO) and wild‑type (WT) control mice were intragastrically administered single doses of alcohol. The plasma concentrations of alanine aminotransferase and aspartate aminotransferase in SHP‑KO mice following alcohol treatment were significantly increased compared with WT mice. However, results of oil red O staining and 2',7'‑dichlorodihydrofluorescein diacetate staining indicated that levels of acute binge drinking‑associated hepatic lipid accumulation and oxidative stress were not significantly different between WT and SHP‑KO alcohol‑treated mice. Notably, tumor necrosis factor‑α mRNA expression in the liver of SHP‑KO mice was significantly increased following alcohol administration, compared with WT mice. Furthermore, the mRNA expression levels of C‑C motif chemokine ligand 2, C‑X‑C motif chemokine ligand 2 and interleukin‑4, which are all potent chemoattractants of NKT cells, as well as neutrophil expression levels, were significantly increased in the livers of SHP‑KO mice compared with WT mice following alcohol administration, as determined by reverse transcription‑quantitative polymerase chain reaction and flow cytometry. Enhanced infiltration of NKT cells, determined by flow cytometry, was also demonstrated in the livers of SHP‑KO mice following alcohol administration, compared with WT mice. The results of the present study indicate that SHP may be involved in liver‑associated protective mechanisms, with regards to the attenuation of damage caused by acute binge drinking, via regulation of NKT cell and neutrophil migration to the liver. The modulation of SHP may be a novel therapeutic strategy for the treatment of acute binge drinking‑induced liver injury.
酗酒在酒精消费者中很常见，可能导致许多疾病的发生，包括肝脏疾病。先前有报道称，自然杀伤 T（NKT）细胞通过促进中性粒细胞浸润诱导酒精相关性肝损伤。在本研究中，研究了孤儿核受体小异二聚体伴侣（SHP）的作用，该蛋白由 NR0B2 基因编码，其在急性 binge 饮酒诱导的肝损伤中的作用。通过胃内给予单次剂量的酒精，对 SHP 敲除（KO）和野生型（WT）对照小鼠进行处理。与 WT 小鼠相比，酒精处理后的 SHP-KO 小鼠血浆丙氨酸氨基转移酶和天冬氨酸氨基转移酶浓度显著升高。然而，油红 O 染色和 2'，7'-二氯二氢荧光素二乙酸酯染色的结果表明，WT 和 SHP-KO 酒精处理小鼠的急性 binge 饮酒相关肝脂质积聚和氧化应激水平没有显著差异。值得注意的是，与 WT 小鼠相比，酒精处理后的 SHP-KO 小鼠肝脏肿瘤坏死因子-α mRNA 表达显著增加。此外，通过逆转录-定量聚合酶链反应和流式细胞术检测到，与 WT 小鼠相比，酒精处理后的 SHP-KO 小鼠肝脏中 C-C 基序趋化因子配体 2、C-X-C 基序趋化因子配体 2 和白细胞介素-4 的 mRNA 表达水平均显著升高，这三种物质均为 NKT 细胞的有效趋化因子，并且中性粒细胞表达水平也显著升高。与 WT 小鼠相比，酒精处理后的 SHP-KO 小鼠肝脏中 NKT 细胞的浸润也明显增强，通过流式细胞术测定。本研究的结果表明，SHP 可能通过调节 NKT 细胞和中性粒细胞向肝脏的迁移，参与与急性 binge 饮酒相关的肝脏保护机制，从而减轻急性 binge 饮酒引起的损伤。SHP 的调节可能是治疗急性 binge 饮酒诱导的肝损伤的一种新的治疗策略。
