MicroRNAs in liver disease.

Abstract

Chronic liver disease refers to a wide group of pathologies caused by several damaging agents and characterized by a slow progression and final development of cirrhosis and hepatocellular carcinoma (HCC). It represents one of the most frequent causes of mortality in Western countries and its increase in last years and the lack of effective treatment highlight the necessity of the better characterization of the disease. Dysregulation of methionine and S-adenosylmethionine (SAMe) metabolism and enzymes participating in the methionine cycle has been implicated in chronic liver disease. Glycine N-methyltransferase (GNMT), the most important SAMe-catabolizing enzyme, is downregulated in liver pathologies such as NAFLD, cholestasis, fibrosis, cirrhosis and HCC. Nevertheless, there are few studies describing its downregulation in liver disease, which may be of interest to develop targeted therapies. We describe novel microRNAs (small non-coding RNAs that regulate gene expression at the posttranscriptional level by mRNA repression) repressing GNMT in chronic liver diseases such as NAFLD, cholestasis and fibrosis and HCC.MiR-873-5p regulates GNMT in NAFLD. Moreover, we describe new functions of mitochondrial GNMT essential for OXPHOS and ß-oxidation processes. Inhibiting this microRNA results in increased cytoplasmic and mitochondrial GNMT levels, enhanced Complex II activity in the ETC and sustained ß-oxidation, avoiding lipid accumulation, inflammation and fibrosis. This microRNA also participates in cholestatic fibrosis, targeting GNMT in hepatocytes, cholangiocytes, inflammatory and fibrogenic cells. Inhibition of miR-873-5p recovers GNMT expression in the different hepatic cell types, avoiding SAMe accumulation and aberrant DNA methylation in the liver, which finally results in an appropriate response and defense against bile acid induced liver damage.Finally, we identify miR-518d-5p is upregulated in HCC acting as an oncomiRs and conferring drug resistance to sorafenib hepatoma cells through the repression of GNMT and c-Jun. Inhibiting this microRNA upregulates the expression of both target genes resulting in increased sorafenib induced apoptosis through mitochondrial dysfunction.