Abstract
The activation of innate immune system is essential for the pathogenesis of nonalcoholic steatohepatitis (NASH). Among pattern recognition receptors, it is well-characterized that toll-like receptors (TLRs) are deeply involved in the development of NASH to reflect exposure of the liver to gut-driven endotoxins. In contrast, it has not been elucidated whether retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) are similarly implicated in the disease progression. In the present study, we examined the expression of melanoma differentiation-associated antigen 5 (MDA5), known to be a member of RLRs, in a diet-induced murine model of NASH. The liver tissues were collected from C57BL/6J mice at 1, 3, and 6weeks after choline-deficient L-amino acid-defined high-fat diet (CDAHFD), and the expression of MDA5 was analyzed by western blotting, immunofluorescence (IF), and real-time quantitative PCR (qPCR). The results of western blotting showed that hepatic expression of MDA5 was increased at 3 and 6weeks. In IF, MDA5-positive cells co-expressed F4/80 and CD11b, indicating they were activated macrophages, and these cells began to appear at 1week after CDAHFD. The mRNA expression of MDA5 was significantly upregulated at 1week. Additionally, we performed IF using liver biopsy specimens collected from 11 patients with nonalcoholic fatty liver diseases (NAFLD), and found that MDA5-positive macrophages were detected in eight out of eleven patients. In an in vitro study, MDA5 was induced upon stimulation with lipopolysaccharide in murine bone marrow-derived macrophages and THP-1 cells. Our findings suggest that MDA5 may be involved in the inflammation of NASH.
Highlights
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases characterized by hepatic damage due to the excessive fat accumulation
We performed IHC using liver biopsy specimens collected from eight patients with nonalcoholic fatty liver diseases (NAFLD), and found that melanoma differentiation-associated antigen 5 (MDA5) was expressed in CD11b-positive macrophages in six out of eight patients
NAFLD consists of nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH), and the latter is a more severe condition that can be a cause of liver cirrhosis and hepatocellular carcinoma (HCC)
Summary
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases characterized by hepatic damage due to the excessive fat accumulation. Hepatic inflammation appears at the same time or prior to steatosis, based on increased adipokines and gut dysbiosis. Adipokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, and leptin released from hypertrophied adipocytes are involved in systemic microinflammation, and in the development of insulin resistance. Intestinal barrier dysfunction and dysbiosis cause exposure of the liver to gut-driven endotoxins via the portal vein [2]. These molecular mechanisms are thought to result in the onset and progression of NASH [3]
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