RT Journal Article T1 Magnesium accumulation upon cyclin M4 silencing activates microsomal triglyceride transfer protein improving NASH. A1 Simón, Jorge A1 Goikoetxea-Usandizaga, Naroa A1 Serrano-Maciá, Marina A1 Fernández-Ramos, David A1 Sáenz de Urturi, Diego A1 Gruskos, Jessica J A1 Fernández-Tussy, Pablo A1 Lachiondo-Ortega, Sofía A1 González-Recio, Irene A1 Rodríguez-Agudo, Rubén A1 Gutiérrez-de-Juan, Virginia A1 Rodríguez-Iruretagoyena, Begoña A1 Varela-Rey, Marta A1 Gimenez-Mascarell, Paula A1 Mercado-Gomez, María A1 Gómez-Santos, Beatriz A1 Fernandez-Rodriguez, Carmen A1 Lopitz-Otsoa, Fernando A1 Bizkarguenaga, Maider A1 Dames, Sibylle A1 Schaeper, Ute A1 Martin, Franz A1 Sabio, Guadalupe A1 Iruzubieta, Paula A1 Crespo, Javier A1 Aspichueta, Patricia A1 Chu, Kevan H-Y A1 Buccella, Daniela A1 Martín, César A1 Delgado, Teresa Cardoso A1 Martínez-Cruz, Luis Alfonso A1 Martínez-Chantar, María Luz K1 CNNM4 K1 Cyclin M4 K1 Endoplasmic reticulum stress K1 MTP K1 Magnesium K1 Microsomal triglyceride transfer protein K1 NASH K1 Non-alcoholic steatohepatitis K1 Therapy K1 siRNA AB Perturbations of intracellular magnesium (Mg2+) homeostasis have implications for cell physiology. The cyclin M family, CNNM, perform key functions in the transport of Mg2+ across cell membranes. Herein, we aimed to elucidate the role of CNNM4 in the development of non-alcoholic steatohepatitis (NASH). Serum Mg2+ levels and hepatic CNNM4 expression were characterised in clinical samples. Primary hepatocytes were cultured under methionine and choline deprivation. A 0.1% methionine and choline-deficient diet, or a choline-deficient high-fat diet were used to induce NASH in our in vivo rodent models. Cnnm4 was silenced using siRNA, in vitro with DharmaFECT and in vivo with Invivofectamine® or conjugated to N-acetylgalactosamine. Patients with NASH showed hepatic CNNM4 overexpression and dysregulated Mg2+ levels in the serum. Cnnm4 silencing ameliorated hepatic lipid accumulation, inflammation and fibrosis in the rodent NASH models. Mechanistically, CNNM4 knockdown in hepatocytes induced cellular Mg2+ accumulation, reduced endoplasmic reticulum stress, and increased microsomal triglyceride transfer activity, which promoted hepatic lipid clearance by increasing the secretion of VLDLs. CNNM4 is overexpressed in patients with NASH and is responsible for dysregulated Mg2+ transport. Hepatic CNNM4 is a promising therapeutic target for the treatment of NASH. Cyclin M4 (CNNM4) is overexpressed in non-alcoholic steatohepatitis (NASH) and promotes the export of magnesium from the liver. The liver-specific silencing of Cnnm4 ameliorates NASH by reducing endoplasmic reticulum stress and promoting the activity of microsomal triglyceride transfer protein. YR 2021 FD 2021-02-09 LK http://hdl.handle.net/10668/17148 UL http://hdl.handle.net/10668/17148 LA en DS RISalud RD Feb 18, 2025