Hepatology (Baltimore, Md.) · 2021
Melanoma differentiation-Associated gene 5 protects against NASH in mice.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Zhang Xin, Yang Hailong, Zeng Shan, Tian Song, Hu Sha, Yang Ling, Ma Tengfei, Liu Zhen, Wan Juan, Zhong Yiming, Li Hongliang
Аннотация
BACKGROUND AND AIMS: NASH is a complicated disease characterized by hepatocyte steatosis, inflammation infiltration, and liver fibrosis. Accumulating evidence suggests that the innate immunity plays a key role in NASH progression. Here, we aimed to reveal the role of melanoma differentiation-associated gene 5 (MDA5, also known as Ifih1), a conventional innate immune regulator following viral infection, in the progression of NASH and investigate its underlying mechanism.
APPROACH AND RESULTS: We first examined the expression of MDA5 and found that MDA5 was markedly down-regulated in the livers with NASH in human individuals and mice models. MDA5 overexpression significantly inhibits the free fatty acid-induced lipid accumulation and inflammation in hepatocyte in vitro, whereas MDA5 knockdown promotes hepatocyte lipotoxicity. Using hepatocyte-specific Mda5 gene knockout and transgenic mice, we found that diet-induced hepatic steatosis, inflammation, and liver fibrosis were markedly exacerbated by Mda5 deficiency but suppressed by Mda5 overexpression. Mechanistically, we found that the activation of apoptosis signal-regulating kinase 1 (ASK1)-mitogen-activated protein kinase pathway was significantly inhibited by MDA5 but enhanced by MDA5 deletion. We further validated that MDA5 directly interacted with ASK1 and suppressed its N-terminal dimerization. Importantly, blockage of ASK1 with adenovirus-expressing dominant negative ASK1 obviously reversed the lipid accumulation and ASK1 pathway activation when Mda5 was knocked out.
CONCLUSIONS: These data indicate that MDA5 is an essential suppressor in NASH. The findings support MDA5 as a regulator of ASK1 and a promising therapeutic target for NASH.
APPROACH AND RESULTS: We first examined the expression of MDA5 and found that MDA5 was markedly down-regulated in the livers with NASH in human individuals and mice models. MDA5 overexpression significantly inhibits the free fatty acid-induced lipid accumulation and inflammation in hepatocyte in vitro, whereas MDA5 knockdown promotes hepatocyte lipotoxicity. Using hepatocyte-specific Mda5 gene knockout and transgenic mice, we found that diet-induced hepatic steatosis, inflammation, and liver fibrosis were markedly exacerbated by Mda5 deficiency but suppressed by Mda5 overexpression. Mechanistically, we found that the activation of apoptosis signal-regulating kinase 1 (ASK1)-mitogen-activated protein kinase pathway was significantly inhibited by MDA5 but enhanced by MDA5 deletion. We further validated that MDA5 directly interacted with ASK1 and suppressed its N-terminal dimerization. Importantly, blockage of ASK1 with adenovirus-expressing dominant negative ASK1 obviously reversed the lipid accumulation and ASK1 pathway activation when Mda5 was knocked out.
CONCLUSIONS: These data indicate that MDA5 is an essential suppressor in NASH. The findings support MDA5 as a regulator of ASK1 and a promising therapeutic target for NASH.