Magnesium accumulation upon cyclin M4 silencing activates microsomal triglyceride transfer protein improving NASH
Year: 2021
Type: article
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.
Language: English
Subfield: Epidemiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: “la Caixa” Foundation, Ministerio de Ciencia, Innovación y Universidades, Eusko Jaurlaritza, Ministerio de Ciencia e Innovación, Banco Bilbao Vizcaya Argentaria, Junta de Andalucía, Silence Therapeutics, National Institutes of Health, Instituto de Salud Carlos III, Berrikuntza + Ikerketa + Osasuna Eusko Fundazioa
Awards: G1299766726, Mch20: Detección de daño hepático a través de la orina, G2118554301, G2290633730, G2342579165, G2661025663, G2749025989, G304302788, G3342290286, G3527378470, G3569586882, G404992930, G4063455850, G4491386922, G4535546208, G4552910358, G4914997810, G526084217, FIGHT-CNNM2: Mejora del diagnóstico y elucidación de los mecanismos patológicos de la Hipomagnesemia rara en pacientes con mutaciones en CNNM2, G5489899341, G5917330134, G6732200646, G6938944540, G7098144862, G7505807458, G8181105605, G8374099137, G8653600395, G945666960
OpenAlex ID: W4287076463