miR-873-5p targets mitochondrial GNMT-Complex II interface contributing to non-alcoholic fatty liver disease

Abstract

Objective Non-alcoholic fatty liver disease (NAFLD) is a complex pathology in which several dysfunctions, including alterations in metabolic pathways, mitochondrial functionality and unbalanced lipid import/export, lead to lipid accumulation and progression to inflammation and fibrosis. The enzyme glycine N-methyltransferase (GNMT), the most important enzyme implicated in S-adenosylmethionine catabolism in the liver, is downregulated during NAFLD progression. We have studied the mechanism involved in GNMT downregulation by its repressor microRNA miR-873-5p and the metabolic pathways affected in NAFLD as well as the benefit of recovery GNMT expression. Methods miR-873-5p and GNMT expression were evaluated in liver biopsies of NAFLD/NASH patients. Different in vitro and in vivo NAFLD murine models were used to assess miR-873-5p/GNMT involvement in fatty liver progression through targeting of the miR-873-5p as NAFLD therapy. Results We describe a new function of GNMT as an essential regulator of Complex II activity in the electron transport chain in the mitochondria. In NAFLD, GNMT expression is controlled by miR-873-5p in the hepatocytes, leading to disruptions in mitochondrial functionality in a preclinical murine non-alcoholic steatohepatitis (NASH) model. Upregulation of miR-873-5p is shown in the liver of NAFLD/NASH patients, correlating with hepatic GNMT depletion. Importantly, NASH therapies based on anti-miR-873-5p resolve lipid accumulation, inflammation and fibrosis by enhancing fatty acid β-oxidation in the mitochondria. Therefore, miR-873-5p inhibitor emerges as a potential tool for NASH treatment. Conclusion GNMT participates in the regulation of metabolic pathways and mitochondrial functionality through the regulation of Complex II activity in the electron transport chain. In NAFLD, GNMT is repressed by miR-873-5p and its targeting arises as a valuable therapeutic option for treatment.

Carnosine alleviates diabetic nephropathy by targeting GNMT, a key enzyme mediating renal inflammation and fibrosis

“…GNMT is an enzyme dependent on S-adenosine l-methionine (SAM) that catalyzes the conversion of glycine to creatine (27)(28)(29). SAM dependent methyltransferases are inhibited by S-adenosyl-L-homocysteine (SAH), and GNMT is believed to play a key role in other methyl transfer reactions as a regulator of the cell SAM/SAH ratio (30,31). GNMT is enriched in liver, kidney and other organs and plays an important role in cell protection (32).…”

Anti-miR-518d-5p overcomes liver tumor cell death resistance through mitochondrial activity

“…The cellular metabolic profile was determined using a Seahorse XFe24 Analyzer (Seahorse Biosciences, USA), providing real-time measurements of the oxygen consumption rate (OCR) as previously described 27 . In total, 7–8 × 10 3 cells were plated and transfected in an XF24 cell culture microplate (Seahorse Bioscience) for 16 h (overnight).…”

“…MiRNAs regulate biological processes including differentiation and metabolism, as well as cellular responses such as proliferation, apoptosis, and tumorigenesis 18 , 19 . In the liver, miRNA signatures have been associated with non-alcoholic fatty liver disease (NAFLD), cirrhosis, and liver cancer 20 – 27 . Different miRNAs have been associated with the development of resistance to chemotherapeutic agents and, notably, to sorafenib 28 – 33 .…”

GNMT: a multifaceted suppressor of hepatocarcinogenesis

“…In the cirrhotic liver of cholestatic patients and animal models of liver cholestasis and cirrhosis, miR-873-5p is inversely correlated with GNMT expression; high circulating miR-873-5 is present in cholestatic patients [80] . The treatment with anti-miR-873-5p in Mdr2-/-mice with bile duct ligation recovers GNMT levels and improves the inflammation and fibrosis by counteracting hepatocyte apoptosis and cholangiocyte proliferation [80] .…”

“…In the cirrhotic liver of cholestatic patients and animal models of liver cholestasis and cirrhosis, miR-873-5p is inversely correlated with GNMT expression; high circulating miR-873-5 is present in cholestatic patients [80] . The treatment with anti-miR-873-5p in Mdr2-/-mice with bile duct ligation recovers GNMT levels and improves the inflammation and fibrosis by counteracting hepatocyte apoptosis and cholangiocyte proliferation [80] . Furthermore, in patients with non-alcoholic fatty liver disease (NAFLD) and a preclinical murine non-alcoholic steatohepatitis (NASH) model, miR-873-5p controls GNMT expression of hepatocytes, leading to the disruption of mitochondrial functionality [81] .…”