Magnesium Accumulation Upon Cyclin M4 Silencing Activates Microsomal Triglyceride Transfer Protein Improving NASH

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-alcohol...

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Detalles Bibliográficos
Autores: 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, Martínez Chantar, María Luz
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universidad del País Vasco
Repositorio:Addi. Archivo Digital para la Docencia y la Investigación
OAI Identifier:oai:addi.ehu.eus:10810/52534
Acceso en línea:http://hdl.handle.net/10810/52534
Access Level:acceso abierto
Palabra clave:non-alcoholic steatohepatitis
NASHCyclin M4
CNNM4
magnesium
therapy
siRNA
endoplasmic reticulum stress
microsomal triglyceride transfer protein
MTP
ER stress
liver
disease
cancer
steatohepatitis
pathogenesis
cells
Descripción
Sumario: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.

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