Glycine N-methyltransferase (GNMT) is the most abundant methyltransferase in the liver and a master regulator of the transmethylation flux. GNMT downregulation leads to loss of liver function progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Moreover, GNMT deficiency aggravates cholestasis-induced fibrogenesis. To date, little is known about the mechanisms underlying downregulation of GNMT levels in hepatic fibrosis and cirrhosis. On this basis, microRNAs are epigenetic regulatory elements that play important roles in liver pathology. In this work, we aim to study the regulation of GNMT by microRNAs during liver fibrosis and cirrhosis. Luciferase assay on the 3ʹUTR-Gnmt was used to confirm in silico analysis showing that GNMT is potentially targeted by the microRNA miR-873-5p. Correlation between GNMT and miR-873-5p in human cholestasis and cirrhosis together with miR-873-5p inhibition in vivo in different mouse models of liver cholestasis and fibrosis [bile duct ligation and Mdr2 (Abcb4)-/- mouse] were then assessed. The analysis of liver tissue from cirrhotic and cholestatic patients, as well as from the animal models, showed that miR-873-5p inversely correlated with the expression of GNMT. Importantly, high circulating miR-873-5p was also detected in cholestastic and cirrhotic patients. Preclinical studies with anti-miR-873-5p treatment in bile duct ligation and Mdr2-/- mice recovered GNMT levels in association with ameliorated inflammation and fibrosis mainly by counteracting hepatocyte apoptosis and cholangiocyte proliferation. In conclusion, miR-873-5p emerges as a novel marker for liver fibrosis, cholestasis, and cirrhosis and therapeutic approaches based on anti-miR-873-5p may be effective treatments for liver fibrosis and cholestatic liver disease.

MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis / Fernández-Ramos, David; Fernández-Tussy, Pablo; Lopitz-Otsoa, Fernando; Gutiérrez-de-Juan, Virginia; Navasa, Nicolás; Barbier-Torres, Lucía; Zubiete-Franco, Imanol; Simón, Jorge; Fernández, Agustín F.; Arbelaiz, Ander; Aransay, Ana M.; Lavín, José Luis; Beraza, Naiara; Perugorria, María J.; Banales, Jesus M.; Villa, Erica; Fraga, Mario F.; Anguita, Juan; Avila, Matias A.; Berasain, Carmen; Iruzibieta, Paula; Crespo, Javier; Lu, Shelly C.; Varela-Rey, Marta; Mato, José M.; Delgado, Teresa C.; Martínez-Chantar, María L.. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 9:10(2018), pp. 958-968. [10.1038/s41419-018-1014-y]

MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis

Villa, Erica;
2018

Abstract

Glycine N-methyltransferase (GNMT) is the most abundant methyltransferase in the liver and a master regulator of the transmethylation flux. GNMT downregulation leads to loss of liver function progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Moreover, GNMT deficiency aggravates cholestasis-induced fibrogenesis. To date, little is known about the mechanisms underlying downregulation of GNMT levels in hepatic fibrosis and cirrhosis. On this basis, microRNAs are epigenetic regulatory elements that play important roles in liver pathology. In this work, we aim to study the regulation of GNMT by microRNAs during liver fibrosis and cirrhosis. Luciferase assay on the 3ʹUTR-Gnmt was used to confirm in silico analysis showing that GNMT is potentially targeted by the microRNA miR-873-5p. Correlation between GNMT and miR-873-5p in human cholestasis and cirrhosis together with miR-873-5p inhibition in vivo in different mouse models of liver cholestasis and fibrosis [bile duct ligation and Mdr2 (Abcb4)-/- mouse] were then assessed. The analysis of liver tissue from cirrhotic and cholestatic patients, as well as from the animal models, showed that miR-873-5p inversely correlated with the expression of GNMT. Importantly, high circulating miR-873-5p was also detected in cholestastic and cirrhotic patients. Preclinical studies with anti-miR-873-5p treatment in bile duct ligation and Mdr2-/- mice recovered GNMT levels in association with ameliorated inflammation and fibrosis mainly by counteracting hepatocyte apoptosis and cholangiocyte proliferation. In conclusion, miR-873-5p emerges as a novel marker for liver fibrosis, cholestasis, and cirrhosis and therapeutic approaches based on anti-miR-873-5p may be effective treatments for liver fibrosis and cholestatic liver disease.
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MiR-873-5p acts as an epigenetic regulator in early stages of liver fibrosis and cirrhosis / Fernández-Ramos, David; Fernández-Tussy, Pablo; Lopitz-Otsoa, Fernando; Gutiérrez-de-Juan, Virginia; Navasa, Nicolás; Barbier-Torres, Lucía; Zubiete-Franco, Imanol; Simón, Jorge; Fernández, Agustín F.; Arbelaiz, Ander; Aransay, Ana M.; Lavín, José Luis; Beraza, Naiara; Perugorria, María J.; Banales, Jesus M.; Villa, Erica; Fraga, Mario F.; Anguita, Juan; Avila, Matias A.; Berasain, Carmen; Iruzibieta, Paula; Crespo, Javier; Lu, Shelly C.; Varela-Rey, Marta; Mato, José M.; Delgado, Teresa C.; Martínez-Chantar, María L.. - In: CELL DEATH & DISEASE. - ISSN 2041-4889. - 9:10(2018), pp. 958-968. [10.1038/s41419-018-1014-y]
Fernández-Ramos, David; Fernández-Tussy, Pablo; Lopitz-Otsoa, Fernando; Gutiérrez-de-Juan, Virginia; Navasa, Nicolás; Barbier-Torres, Lucía; Zubiete-Franco, Imanol; Simón, Jorge; Fernández, Agustín F.; Arbelaiz, Ander; Aransay, Ana M.; Lavín, José Luis; Beraza, Naiara; Perugorria, María J.; Banales, Jesus M.; Villa, Erica; Fraga, Mario F.; Anguita, Juan; Avila, Matias A.; Berasain, Carmen; Iruzibieta, Paula; Crespo, Javier; Lu, Shelly C.; Varela-Rey, Marta; Mato, José M.; Delgado, Teresa C.; Martínez-Chantar, María L.
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