Department of Physiology, University of the Basque Country Medical School, Bilbao, Spain.
Hepatology. 2011 Dec;54(6):1975-86. doi: 10.1002/hep.24607.
Very low-density lipoprotein (VLDL) secretion provides a mechanism to export triglycerides (TG) from the liver to peripheral tissues, maintaining lipid homeostasis. In nonalcoholic fatty liver disease (NAFLD), VLDL secretion disturbances are unclear. Methionine adenosyltransferase (MAT) is responsible for S-adenosylmethionine (SAMe) synthesis and MAT I and III are the products of the MAT1A gene. Deficient MAT I and III activities and SAMe content in the liver have been associated with NAFLD, but whether MAT1A is required for normal VLDL assembly remains unknown. We investigated the role of MAT1A on VLDL assembly in two metabolic contexts: in 3-month-old MAT1A-knockout mice (3-KO), with no signs of liver injury, and in 8-month-old MAT1A-knockout mice (8-KO), harboring nonalcoholic steatohepatitis. In 3-KO mouse liver, there is a potent effect of MAT1A deletion on lipid handling, decreasing mobilization of TG stores, TG secretion in VLDL and phosphatidylcholine synthesis via phosphatidylethanolamine N-methyltransferase. MAT1A deletion also increased VLDL-apolipoprotein B secretion, leading to small, lipid-poor VLDL particles. Administration of SAMe to 3-KO mice for 7 days recovered crucial altered processes in VLDL assembly and features of the secreted lipoproteins. The unfolded protein response was activated in 8-KO mouse liver, in which TG accumulated and the phosphatidylcholine-to-phosphatidylethanolamine ratio was reduced in the endoplasmic reticulum, whereas secretion of TG and apolipoprotein B in VLDL was increased and the VLDL physical characteristics resembled that in 3-KO mice. MAT1A deletion also altered plasma lipid homeostasis, with an increase in lipid transport in low-density lipoprotein subclasses and decrease in high-density lipoprotein subclasses.
MAT1A is required for normal VLDL assembly and plasma lipid homeostasis in mice. Impaired VLDL synthesis, mainly due to SAMe deficiency, contributes to NAFLD development in MAT1A-KO mice.
极低密度脂蛋白 (VLDL) 的分泌提供了一种从肝脏向外周组织输出甘油三酯 (TG) 的机制，维持着脂质的体内平衡。在非酒精性脂肪性肝病 (NAFLD) 中，VLDL 分泌紊乱尚不清楚。甲硫氨酸腺苷转移酶 (MAT) 负责 S-腺苷甲硫氨酸 (SAMe) 的合成，MAT I 和 III 是 MAT1A 基因的产物。肝脏中 MAT I 和 III 活性和 SAMe 含量的降低与 NAFLD 有关，但 MAT1A 是否是正常 VLDL 组装所必需的仍不清楚。我们在两种代谢环境中研究了 MAT1A 对 VLDL 组装的作用：在 3 个月大的 MAT1A 敲除小鼠 (3-KO) 中，没有肝脏损伤的迹象，和在 8 个月大的 MAT1A 敲除小鼠 (8-KO) 中，有非酒精性脂肪性肝炎。在 3-KO 小鼠肝脏中，MAT1A 缺失对脂质代谢有显著影响，降低了 TG 储存的动员、VLDL 中的 TG 分泌和通过磷酸乙醇胺 N-甲基转移酶合成的磷酸胆碱。MAT1A 缺失还增加了 VLDL-载脂蛋白 B 的分泌，导致小而脂质贫乏的 VLDL 颗粒。在 3-KO 小鼠中给予 SAMe 治疗 7 天，恢复了 VLDL 组装过程中的关键改变和分泌脂蛋白的特征。未折叠蛋白反应在 8-KO 小鼠肝脏中被激活，其中 TG 在肝内积累，内质网中磷酸胆碱与磷酸乙醇胺的比例降低，而 TG 和载脂蛋白 B 在 VLDL 中的分泌增加，VLDL 的物理特征类似于 3-KO 小鼠。MAT1A 缺失还改变了血浆脂质的体内平衡，使 LDL 亚类中的脂质转运增加，HDL 亚类中的脂质转运减少。
MAT1A 是小鼠正常 VLDL 组装和血浆脂质体内平衡所必需的。由于 SAMe 缺乏，VLDL 合成受损，导致 MAT1A-KO 小鼠的 NAFLD 发展。
