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.

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.

• Authors: Xin Zhang, Hailong Yang, Shan Zeng, Song Tian, Sha Hu, Ling Yang, Tengfei Ma, Zhen Liu, Juan Wan, Yiming Zhong, Hongliang Li
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 75 Issue 4 Pg. 924-938 (04 2022) ISSN: 1527-3350 [Electronic] United States
• PMID: 34482560 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 American Association for the Study of Liver Diseases.

Chemical References

• Lipids

Topics

• Animals
• Inflammation (complications)
• Lipids (therapeutic use)
• Liver (metabolism)
• Liver Cirrhosis (complications, genetics, prevention & control)
• Melanoma
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Non-alcoholic Fatty Liver Disease (etiology)