脂肪变性
非酒精性脂肪肝
内科学
纤维化
内分泌学
炎症
肝细胞
脂肪肝
脂肪性肝炎
生物
医学
疾病
生物化学
体外
作者
Lindsey Kennedy,Vik Meadows,Amelia Sybenga,Jennifer Demieville,Lixian Chen,Laura Hargrove,Burcin Ekser,Wasim Dar,Ludovica Ceci,Debjyoti Kundu,Konstantina Kyritsi,Linh Pham,Tianhao Zhou,Shannon Glaser,Fanyin Meng,Gianfranco Alpini,Heather Francis
出处
期刊:Hepatology
[Wiley]
日期:2021-05-24
卷期号:74 (1): 164-182
被引量:23
摘要
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 KitW-sh (MC-deficient) mice were fed a control diet (CD) or a Western diet (WD) for 16 weeks; select WT and KitW-sh 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 KitW-sh 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 KitW-sh WD mice. MicroRNA 144-3 prime (miR-144-3p) expression was increased in WT WD mice and human NASH but reduced in KitW-sh 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.
科研通智能强力驱动
Strongly Powered by AbleSci AI