Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN.
Hepatology. 2021 Jul;74(1):164-182. doi: 10.1002/hep.31713. Epub 2021 May 24.
Nonalcoholic fatty liver disease (NAFLD) is simple steatosis but can develop into nonalcoholic steatohepatitis (NASH), characterized by liver inflammation, fibrosis, and microvesicular steatosis. Mast cells (MCs) infiltrate the liver during cholestasis and promote ductular reaction (DR), biliary senescence, and liver fibrosis. We aimed to determine the effects of MC depletion during NAFLD/NASH.
Wild-type (WT) and Kit (MC-deficient) mice were fed a control diet (CD) or a Western diet (WD) for 16 weeks; select WT and Kit WD mice received tail vein injections of MCs 2 times per week for 2 weeks prior to sacrifice. Human samples were collected from normal, NAFLD, or NASH mice. Cholangiocytes from WT WD mice and human NASH have increased insulin-like growth factor 1 expression that promotes MC migration/activation. Enhanced MC presence was noted in WT WD mice and human NASH, along with increased DR. WT WD mice had significantly increased steatosis, DR/biliary senescence, inflammation, liver fibrosis, and angiogenesis compared to WT CD mice, which was significantly reduced in Kit WD mice. Loss of MCs prominently reduced microvesicular steatosis in zone 1 hepatocytes. MC injection promoted WD-induced biliary and liver damage and specifically up-regulated microvesicular steatosis in zone 1 hepatocytes. Aldehyde dehydrogenase 1 family, member A3 (ALDH1A3) expression is reduced in WT WD mice and human NASH but increased in Kit WD mice. MicroRNA 144-3 prime (miR-144-3p) expression was increased in WT WD mice and human NASH but reduced in Kit WD mice and was found to target ALDH1A3.
MCs promote WD-induced biliary and liver damage and may promote microvesicular steatosis development during NAFLD progression to NASH through miR-144-3p/ALDH1A3 signaling. Inhibition of MC activation may be a therapeutic option for NAFLD/NASH treatment.
非酒精性脂肪性肝病（NAFLD）仅是单纯性脂肪变性，但可发展为非酒精性脂肪性肝炎（NASH），其特征为肝脏炎症、纤维化和微泡性脂肪变性。在胆汁淤积时，肥大细胞（MCs）浸润肝脏并促进胆管反应（DR）、胆管衰老和肝纤维化。本研究旨在确定 NAFLD/NASH 期间 MC 耗竭的作用。
野生型（WT）和 Kit（MC 缺陷型）小鼠分别用对照饮食（CD）或西方饮食（WD）喂养 16 周；选择 WT 和 Kit WD 小鼠在处死前 2 周每周接受两次尾静脉注射 MC。从正常、NAFLD 或 NASH 小鼠中收集人样本。WT WD 小鼠的胆管细胞和人 NASH 的胰岛素样生长因子 1 表达增加，促进 MC 迁移/激活。在 WT WD 小鼠和人 NASH 中观察到增强的 MC 存在，以及增加的 DR。与 WT CD 小鼠相比，WT WD 小鼠显著增加了脂肪变性、DR/胆管衰老、炎症、肝纤维化和血管生成，而 Kit WD 小鼠则显著减少。MC 耗竭明显减少了 1 区肝细胞的微泡性脂肪变性。MC 注射促进 WD 诱导的胆管和肝损伤，并特异性地上调了 1 区肝细胞的微泡性脂肪变性。醛脱氢酶 1 家族成员 A3（ALDH1A3）在 WT WD 小鼠和人 NASH 中表达减少，但在 Kit WD 小鼠中表达增加。miR-144-3 前体（miR-144-3p）在 WT WD 小鼠和人 NASH 中表达增加，但在 Kit WD 小鼠中表达减少，并且发现其靶向 ALDH1A3。
MC 通过 miR-144-3p/ALDH1A3 信号促进 WD 诱导的胆管和肝脏损伤，并可能促进 NAFLD 进展为 NASH 期间的微泡性脂肪变性发展。MC 激活的抑制可能是治疗 NAFLD/NASH 的一种选择。
