Magnesium accumulation upon cyclin M4 silencing activates microsomal triglyceride transfer protein improving NASH

Jorge Simón, Naroa Goikoetxea-Usandizaga, Marina Serrano-Maciá, David Fernández-Ramos, Diego Sáenz de Urturi, Jessica J. Gruskos, Pablo Fernández-Tussy, Sofía Lachiondo-Ortega, Irene González-Recio, Rubén Rodríguez-Agudo, Virginia Gutiérrez-de-Juan, Begoña Rodríguez-Iruretagoyena, Marta Varela-Rey, Paula Gimenez-Mascarell, María Mercado-Gomez, Beatriz Gómez-Santos, Carmen Fernandez-Rodriguez, Fernando Lopitz-Otsoa, Maider Bizkarguenaga, Sibylle DamesUte Schaeper, Franz Martin, Guadalupe Sabio, Paula Iruzubieta, Javier Crespo, Patricia Aspichueta, Kevan H.Y. Chu, Daniela Buccella, César Martín, Teresa Cardoso Delgado, Luis Alfonso Martínez-Cruz, María Luz Martínez-Chantar

Research output: Contribution to journalArticlepeer-review

Abstract

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® or conjugated to N-acetylgalactosamine. Results: 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. 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 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.

Original languageEnglish (US)
JournalJournal of Hepatology
DOIs
StateAccepted/In press - 2021

Keywords

  • CNNM4
  • Cyclin M4
  • Endoplasmic reticulum stress
  • MTP
  • Magnesium
  • Microsomal triglyceride transfer protein
  • NASH
  • Non-alcoholic steatohepatitis
  • Therapy
  • siRNA

ASJC Scopus subject areas

  • Hepatology

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