(The) roles of glutamate and mitochondrial double-stranded rna in chronic liver diseases

Abstract

Liver fibrosis and cancer are irreversible stages in the broad spectrum of chronic liver disease, including steatosis and inflammation. However, there are no curative options in the hepatic fibrosis and tumor. In this study, I reported the alteration of liver fibrosis and cancer with hepatocyte originated glutamate and mitochondrial double-stranded RNA (mtdsRNA) in exosome. Liver fibrosis was induced by administration of carbon tetrachloride and liver cancer was developed by diethylnitrosamine injection in mouse model. Genetic depletion of metabotropic glutamtate receptor 5 (mGluR5) aggravated liver fibrosis and pharmacologic activation of the receptor alleviated fibrotic chracteristics in mouse liver. In vitro, activation of mGluR5 in natural killer (NK) cells augmented cytotoxicity against hepatic stellate cells, which are known to be crucial in the development of liver fibrogenesis. Conditional knockout of mGluR5 in NK cells also increased the severity of liver fibrosis with carbon tetrachloride. Meanwhile, treatement of exosomes to macrophages increased the expression of toll-like receptor 3 (TLR3), which recognize double-stranded RNA, and protumoral cytokine, such as interleukin-10. Genetic depletion of TLR3 in mice alleviated tumorigenesis of liver. In addition, macrophages were mainly infiltrated in the adjacent area to the tumor of TLR3 knockout mice. Mitochondrial contents were upregulated in the exosome derived from serum and liver tissue from liver cancer induced mice. In conclusion, glutamate and activation of its receptor could ameliorate liver fibrosis, and mtdsRNA in exosome induce protumoral feature of macrophages in liver. Therefore, alteration of liver glutamate and mtdsRNA could be treatment options for liver fibrosis and cancer, which are the important health problems worldwide.