Magnesium accumulation upon cyclin M4 silencing activates microsomal triglyceride transfer protein improving NASH.
Magnesium accumulation upon cyclin M4 silencing activates microsomal triglyceride transfer protein improving NASH.
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DOI：
10.1016/j.jhep.2021.01.043
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发表时间：
2021-07
影响因子：
25.7
通讯作者：
Martínez-Chantar ML
中科院分区：
文献类型：
--
作者：
Simón J;Goikoetxea-Usandizaga N;Serrano-Maciá M;Fernández-Ramos D;Sáenz de Urturi D;Gruskos JJ;Fernández-Tussy P;Lachiondo-Ortega S;González-Recio I;Rodríguez-Agudo R;Gutiérrez-de-Juan V;Rodríguez-Iruretagoyena B;Varela-Rey M;Gimenez-Mascarell P;Mercado-Gomez M;Gómez-Santos B;Fernandez-Rodriguez C;Lopitz-Otsoa F;Bizkarguenaga M;Dames S;Schaeper U;Martin F;Sabio G;Iruzubieta P;Crespo J;Aspichueta P;Chu KH;Buccella D;Martín C;Delgado TC;Martínez-Cruz LA;Martínez-Chantar ML
细胞内镁（Mg 2+）稳态的扰动对细胞生理学有影响。细胞周期蛋白M家族，CNNM，在Mg 2+跨细胞膜转运中起关键作用。在此，我们旨在阐明CNNM 4在非酒精性脂肪性肝炎（NASH）发展中的作用。在临床样品中表征血清Mg 2+水平和肝CNNM 4表达。原代肝细胞在甲硫氨酸和胆碱剥夺下培养。在我们的体内啮齿动物模型中，使用0.1%甲硫氨酸和胆碱缺乏饮食或胆碱缺乏高脂肪饮食诱导NASH。Cnnm 4使用siRNA沉默，在体外用DharmaFECT沉默，在体内用Invivofectamine®沉默或与N-乙酰半乳糖胺缀合。NASH患者显示肝脏CNNM 4过表达和血清中Mg 2+水平失调。Cnnm 4沉默改善啮齿动物NASH模型中的肝脂质积累、炎症和纤维化。从机制上讲，肝细胞中CNNM 4敲低诱导细胞Mg 2+蓄积，降低内质网应激，并增加微粒体甘油三酯转移活性，这通过增加VLDL分泌促进肝脏脂质清除。CNNM 4在NASH患者中过表达，并导致Mg 2+转运失调。肝脏CNNM 4是治疗NASH的一个有前途的治疗靶点。细胞周期蛋白M4（CNNM 4）在非酒精性脂肪性肝炎（NASH）中过表达，并促进镁从肝脏输出。Cnnm 4的肝脏特异性沉默通过减少内质网应激和促进微粒体甘油三酯转移蛋白的活性来改善NASH。
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). 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. 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. 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. 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.
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