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

Abstract Background and 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. Methods Clinical characterization of serum Mg2+ levels and hepatic CNNM4 expression. Primary hepatocytes cultured under methionine and choline deprivation. In vivo rodent NASH models: 0.1% methionine and choline-deficient and choline-deficient high-fat diets. 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 very-low-density lipoprotein. Conclusions Hepatic CNNM4 is a valuable therapeutic target for treating NASH.