Magnesium Accumulation Upon Cyclin M4 Silencing Activates Microsomal Triglyceride Transfer Protein Improving NASH
Ikusi/ Ireki
Data
2021-07Egilea
Simón Espinosa, Jorge
Goikoetxea Usandizaga, Naroa
Serrano Maciá, Marina
Fernández Ramos, David
Saenz de Urturi Indart, Diego
Gruskos, Jessica J.
Fernández Tussy, Pablo
Lachiondo Ortega, Sofía
González Recio, Irene
Rodríguez Agudo, Rubén
Gutiérrez de Juan, Virginia
Rodríguez Iruretagoyena, Begoña
Varela Rey, Marta
Giménez Mascarell, Paula
Mercado Gómez, María
Gómez Santos, Beatriz
Fernández Rodríguez, Carmen
Lopitz Otsoa, Fernando
Bizkarguenaga, Maider
Dames, Sibylle
Schaeper, Ute
Martin, Franz
Sabio, Guadalupe
Iruzubieta, Paula
Crespo, Javier
Aspichueta Celaá, Patricia
Chu, Kevan H. Y.
Buccella, Daniela
Martín Plágaro, César Augusto
Cardoso Delgado, Teresa de Jesús
Martínez de la Cruz, Alfonso
Journal Of Hepatology 75(1) : 34-45 (2021)
Laburpena
Background & Aims: 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).
Methods: 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 (R) or conjugated to N-acetylgalactosamine.
Results: Patients with NASH showed hepatic CNNM4 over-expression 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.
Conclusions: 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.
Lay summary: Cyclin M4 (CNNM4) is overexpressed in nonalcoholic 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.