Department of Physiology, School of Medicine, University of Louisville, Louisville, KY, United States.
Department of Medicine, School of Medicine, University of Louisville, Louisville, KY, United States.
Front Immunol. 2024 Feb 1;15:1316228. doi: 10.3389/fimmu.2024.1316228. eCollection 2024.
It is well established that females are more susceptible to the toxic effects of alcohol, although the exact mechanisms are still poorly understood. Previous studies noted that alcohol reduces the expression of mitogen-activated protein kinase phosphatase 1 (MKP1), a negative regulator of mitogen-activated protein kinases (MAPK) in the liver. However, the role of hepatocyte- specific MKP1 in the pathogenesis of alcohol-associated liver disease (ALD) remains uncharacterized. This study aimed to evaluate the role of hepatocyte-specific MKP1 in the susceptibility and sexual dimorphism in alcohol-induced liver injury.
C57Bl/6 mice were used in an intragastric ethanol feeding model of alcohol-associated steatohepatitis (ASH). Hepatocyte-specific knockout and ( "f/f" male and female mice were subjected to the NIAAA chronic plus binge model. Primary mouse hepatocytes were used for studies. Liver RNA sequencing was performed on an Illumina NextSeq 500. Liver injury was evaluated by plasma alanine transaminase (ALT), hepatic ER stress and inflammation markers. Statistical analysis was carried out using ANOVA and the unpaired Student's t-test.
ASH was associated with the severe injury accompanied by increased endoplasmic reticulum (ER) stress and significant downregulation of mRNA expression. , ethanol treatment resulted in a time-dependent decrease in mRNA and protein expression in primary hepatocytes in both males and females; however, this effect was significantly more pronounced in hepatocytes from females. , female mice developed more liver injury in a chronic plus binge model which was accompanied by a significant decrease in liver mRNA expression. In comparison, liver was not changed in male mice, while they developed milder injury to alcohol. deletion in hepatocytes led to increased alcohol induced liver injury, ER stress and inflammation in both sexes.
Hepatocyte Mkp1 plays a significant role in alcohol induced liver injury. Alcohol downregulates Mkp1 expression in hepatocytes in a sex dependent manner and could play a role in sexual dimorphism in increased female susceptibility to alcohol.
众所周知，女性对酒精的毒性作用更为敏感，尽管确切的机制仍知之甚少。先前的研究表明，酒精会降低丝裂原激活蛋白激酶磷酸酶 1（MKP1）的表达，MKP1 是肝脏中丝裂原激活蛋白激酶（MAPK）的负调节剂。然而，肝特异性 MKP1 在酒精相关性肝病（ALD）发病机制中的作用仍未被描述。本研究旨在评估肝特异性 MKP1 在酒精诱导的肝损伤易感性和性别二态性中的作用。
使用 C57Bl/6 小鼠进行酒精相关性脂肪性肝炎（ASH）的胃内乙醇喂养模型。肝特异性 敲除和（"f/f"雄性和雌性小鼠接受 NIAAA 慢性加 binge 模型。使用原代小鼠肝细胞进行研究。使用 Illumina NextSeq 500 进行肝 RNA 测序。通过血浆丙氨酸转氨酶（ALT）、肝内质网应激和炎症标志物评估肝损伤。使用方差分析和未配对学生 t 检验进行统计分析。
ASH 与严重损伤相关，伴有内质网（ER）应激增加和显著下调 mRNA 表达。此外，乙醇处理导致雄性和雌性原代肝细胞中 mRNA 和蛋白表达随时间减少；然而，这种影响在雌性肝细胞中更为明显。雌性小鼠在慢性加 binge 模型中发展出更严重的肝损伤，同时肝 mRNA 表达显著降低。相比之下，雄性小鼠的肝 没有变化，而它们对酒精的损伤较轻。肝特异性 Mkp1 缺失导致两性酒精诱导的肝损伤、内质网应激和炎症增加。
肝 Mkp1 在酒精诱导的肝损伤中起重要作用。酒精以性别依赖的方式下调肝细胞中的 Mkp1 表达，并可能在女性对酒精的易感性增加的性别二态性中发挥作用。
