Melanoma differentiation—Associated gene 5 protects against NASH in mice

Abstract

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.

Osteoprotegerin deficiency aggravates methionine–choline-deficient diet-induced nonalcoholic steatohepatitis in mice

“…Three well-characterized MAPK subfamilies are p38, JNK, and ERK1/2, which are related to NASH development. MAPK can be activated by upstream kinase signals, such as apoptosis signal-regulated kinase 1 and mixed-spectrum kinase 3 34,35 . By contrast, MAPKs are inactivated through direct dephosphorylation of their threonine and tyrosine residues by a set of bispecific protein tyrosines [36][37][38] .…”

CCN6 improves hepatic steatosis, inflammation, and fibrosis in non‐alcoholic steatohepatitis

“…ASK1 is a mitogen‐activated protein kinase kinase kinase (MAP3K), and widely expressed in tissue and cells that regulates the MAPK pathways through homodimerization and subsequent autophosphorylation in response to stressful stimuli from various sources including ROS, endoplasmic reticulum stress, bacterial and viral infections, calcium inward flow, and inflammatory signals 33 . Numerous studies have demonstrated that overactivation of the ASK1/JNK/p38 pathway in the liver of NASH plays an important role in disease progression and that inhibition of ASK1 attenuates insulin resistance, inflammation and hepatic lipid accumulation in NASH 35–38 . Although some clinical trials on the treatment of NASH with small molecule inhibitors of ASK1 have not reached definitive endpoints yet, the current efforts of the researchers to treat NASH and its related complications by interfering with ASK1 have never been stopped 31,32 .…”

“…33 Numerous studies have demonstrated that overactivation of the ASK1/JNK/p38 pathway in the liver of NASH plays an important role in disease progression and that inhibition of ASK1 attenuates insulin resistance, inflammation and hepatic lipid accumulation in NASH. [35][36][37][38] Although some clinical trials on the treatment of NASH with small molecule inhibitors of ASK1 have not reached definitive endpoints yet, the current efforts of the researchers to treat NASH and its related complications by interfering with ASK1 have never been stopped. 31,32 Collectively, our findings provide new insight into the mode of action of key negative regulators of NASH as ASK1, thus paving the way for clinical translation of basic discoveries.…”

Osteoprotegerin deficiency aggravates methionine- choline- deficient diet-induced nonalcoholic steatohepatitis in mice

“…Three well-characterized MAPK subfamilies are p38, JNK, and ERK1/2, which are related to NASH development. MAPK can be activated by upstream kinase signals, such as apoptosis signal-regulated kinase 1 and mixed-spectrum kinase 3 31,32 . By contrast, MAPKs are inactivated through direct dephosphorylation of their threonine and tyrosine residues by a set of bispeci c protein tyrosines [33][34][35] .…”