microRNA‐143‐3p attenuated development of hepatic fibrosis in autoimmune hepatitis through regulation of TAK1 phosphorylation

Abstract

Autoimmune hepatitis (AIH) is a chronic liver disease due to autoimmune system attacks hepatocytes and causes inflammation and fibrosis. Intracellular signalling and miRNA may play an important role in regulation of liver injury. This study aimed to investigate the potential roles of microRNA 143 in a murine AIH model and a hepatocyte injury model. Murine AIH model was induced by hepatic antigen S100, and hepatocyte injury model was induced by LPS. Mice and AML12 cells were separated into six groups with or without the treatment of miRNA-143. Inflammation and fibrosis as well as gene expression were examined by different cellular and molecular techniques. The model was successfully established with the elevation of ALT and AST as well as inflammatory and fibrotic markers. Infection or transfection of mir-143 in mice or hepatocytes significantly attenuated the development of alleviation of hepatocyte injury. Moreover, the study demonstrated phosphorylation of TAK1-mediated miRNA-143 regulation of hepatic inflammation and fibrosis as well as hepatocyte injury. Our studies demonstrated a significant role of miRNA-143 in attenuation of liver injury in AIH mice and hepatocytes. miRNA-143 regulates inflammation and fibrosis through its regulation of TAK1 phosphorylation, which warrants TAK1 as a target for the development of new therapeutic strategy of autoimmune hepatitis. K E Y W O R D S autoimmune hepatitis, gene therapy, liver fibrosis, miR-143, TAK1 | 1257 TU eT al.

Ubiquitously specific protease 4 inhibitor‐Vialinin A attenuates inflammation and fibrosis in S100‐induced hepatitis mice through Rheb/mTOR signalling

“…Ubiquitination generates a targeting signal that can be used to alter the properties or localization of the ubiquitinated protein and delivered ubiquitinated proteins to the proteasome, a large compartmentalized multi-catalytic protease that is responsible for much of the regulated proteolysis in cells. 17 However, USP4 as an deubiquitinating enzymes reverses the ubiquitination. With the regulatory role of deubiquitination in inflammation reaction is highly valued, a key role for the deubiquitinase USP4 has been reported in some liver disease.…”

“…The protocol of inducing autoimmune hepatitis with S100 7,17 was listed in Figure 1A. As shown in Figure 1, there were significant increases in ALT and AST values in AIH mice ( Figure 1B).…”

The Differential and Dynamic Progression of Hepatic Inflammation and Immune Responses During Liver Fibrosis Induced by Schistosoma japonicum or Carbon Tetrachloride in Mice

“…ALT exists in the cytoplasm of hepatocytes and is released into the blood when they are damaged; therefore, ALT was assayed to reflect the damage to hepatocytes ( 26 ). Hydroxyproline levels correlate significantly with liver fibrosis ( 27 ) and its level could reflect the intensity of fibrosis.…”

Diagnosis and Therapeutic Management of Liver Fibrosis by MicroRNA

“…miR-674-5p may ameliorate liver injury by negatively regulating the expression of 5-LO [ 107 ]. miRNA-143 regulates inflammation and fibrosis by regulating the phosphorylation of TGF-β-activated kinase 1 (TAK1) [ 108 ]. miRNAs modulate apoptosis and inflammatory reactions by affecting macrophages, regulatory T cells, Th17 cells, CD4 + T cells, and hepatocytes [ 67 ].…”