Department of Infectious Diseases, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China.
Bone and Joint Surgery, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China.
Hum Exp Toxicol. 2021 Oct;40(10):1634-1645. doi: 10.1177/09603271211002886. Epub 2021 Mar 29.
To explore the effects of myocardin-related transcription factor A (MRTF-A) knockout on mice with nonalcoholic steatohepatitis (NASH) induced by high-fat diet (HFD).
Normal-fat diet (NFD) or HFD was fed to MRTF-A-knockout (MRTF-A) and wild-type (WT) mice for 16 weeks. Liver histopathological status was observed using Hematoxylin and Eosin (HE) staining, Oil Red O staining, Sirius Red staining, and Immunohistochemical staining. The mRNA and protein levels in liver tissues were measured through quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot.
Compared with WT + HFD group, mice in MRTF-A + HFD group were decreased in body weight, blood glucose, plasma insulin, liver TG and NAFLD activity score (NAS), with liver function recovery. Besides, compared with HFD-fed WT mice, HFD-fed MRTF-A mice were improved in hepatic fibrosis, accompanied by decreased collagen content (%) and down-regulated expressions of , and . In mice fed with HFD, the expression of MCP-1, CCR2, F4/80 and CD68 declined in liver tissues of MRTF-A mice as compared with WT mice. Besides, in hepatic macrophages isolated from HFD-fed mice, the observed increased expression of , , , as well as decreased expression of CCR2. Compared with WT + HFD group, MRTF-A + HFD group mice were decreased regarding NF-κB p65 in liver tissues.
MRTF-A knockout reduced macrophage infiltration, down-regulated NF-κB p65 expression, and ameliorated inflammation and fibrosis of liver tissues in mice, thereby becoming a potential therapeutic target for NASH treatment.
探讨肌球蛋白相关转录因子 A（MRTF-A）敲除对高脂肪饮食（HFD）诱导的非酒精性脂肪性肝炎（NASH）小鼠的影响。
给予 MRTF-A 敲除（MRTF-A）和野生型（WT）小鼠正常脂肪饮食（NFD）或 HFD，喂养 16 周。采用苏木精和伊红（HE）染色、油红 O 染色、天狼星红染色和免疫组织化学染色观察肝组织病理状态。通过定量逆转录聚合酶链反应（qRT-PCR）和 Western blot 测量肝组织中的 mRNA 和蛋白水平。
与 WT + HFD 组相比，MRTF-A + HFD 组小鼠体重、血糖、血浆胰岛素、肝甘油三酯和非酒精性脂肪性肝病活动评分（NAS）降低，肝功能恢复。此外，与 HFD 喂养的 WT 小鼠相比，MRTF-A 喂养的 HFD 小鼠肝纤维化得到改善，胶原含量（%）降低，和下调。在 HFD 喂养的小鼠中，与 WT 小鼠相比，MRTF-A 小鼠肝组织中 MCP-1、CCR2、F4/80 和 CD68 的表达降低。此外，在 HFD 喂养的肝巨噬细胞中，观察到、、和 CCR2 的表达增加，而表达减少。与 WT + HFD 组相比，MRTF-A + HFD 组小鼠肝组织中 NF-κB p65 减少。
MRTF-A 敲除减少了巨噬细胞浸润，下调了 NF-κB p65 的表达，改善了肝组织的炎症和纤维化，因此成为 NASH 治疗的潜在治疗靶点。
