BUSCADOR RECOLECTA

Digital.CSIC. Repositorio Institucional del CSIC

oai:digital.csic.es:10261/188345

Título del pdf-manuscrito: PGE2 attenuates liver fibrosis in mice by downregulating miR-23a- 5p and inducing apoptosis of hepatic stellate cells., MicroRNAs (miRNAs), small noncoding RNAs modulating messenger RNA (mRNA) and protein expression, have emerged as key regulatory molecules in chronic liver diseases, whose end stage is hepatic fibrosis, a major global health burden. Pharmacological strategies for prevention or treatment of hepatic fibrosis are still limited, what makes it necessary to establish a better understanding of the molecular mechanisms underlying its pathogenesis. In this context, we have recently shown that cyclooxygenase-2 (COX-2) expression in hepatocytes restricts activation of hepatic stellate cells (HSCs), a pivotal event in the initiation and progression of hepatic fibrosis. Here, we evaluated the role of COX-2 in the regulation of a specific set of miRNAs on a mouse model of CCl4 and bile duct ligation (BDL)-induced liver fibrosis. Our results provide evidence that COX-2 represses miR-23a-5p and miR-28-5p expression in HSC. The decrease of miR-23a-5p and miR-28-5p expression promotes protection against fibrosis by decreasing the levels of pro-fibrogenic markers α-SMA and COL1A1 and increasing apoptosis of HSC. Moreover, we demonstrate that serum levels of miR-28-5p are decreased in patients with chronic liver disease. These results suggest a protective effect exerted by COX-2-derived prostanoids in the process of hepatofibrogenesis., This work was supported by Financing Program for short stays abroad for Assistant Researchers (CONICET-Argentina) and i-COOP2016-20213 to D.F.; SAF2014-52492 (MINECO, Spain) to L.B.; CIBERcv and CIBERehd (ISCIII, Spain) to L.B., P.M.S. and M.C.; PI13/01299 (ISCIII, Spain) to C.G-M.; SAF2013-43713-R, SAF2016-75004-R and SAF2015-70270-REDT (MINECO, Spain) to L.B., P.M.S. and M.C. We thank FEDER for financial support., Peer reviewed