School of Graduate Studies, Molecular and Cell Biology Program, State University of New York Downstate Medical Center, Brooklyn, New York 11203; Departments of Cell Biology and Pediatrics, State University of New York Downstate Medical Center, Brooklyn, New York 11203.
Departments of Cell Biology and Pediatrics, State University of New York Downstate Medical Center, Brooklyn, New York 11203.
J Biol Chem. 2013 May 17;288(20):14372-14383. doi: 10.1074/jbc.M113.459602. Epub 2013 Mar 26.
Microsomal triglyceride transfer protein (MTP) is a target to reduce plasma lipids because of its indispensable role in triglyceride-rich lipoprotein biosynthesis. MTP inhibition in Western diet fed mice decreased plasma triglycerides/cholesterol, whereas increasing plasma alanine/aspartate aminotransferases (ALT/AST) and hepatic triglycerides/free cholesterol. Free cholesterol accumulated in the endoplasmic reticulum (ER) and mitochondria resulting in ER and oxidative stresses. Mechanistic studies revealed that MTP inhibition increased transcription of the GPT/GOT1 genes through up-regulation of the IRE1α/cJun pathway leading to increased synthesis and release of ALT1/AST1. Thus, transcriptional up-regulation of GPT/GOT1 genes is a major mechanism, in response to ER stress, elevating plasma transaminases. Increases in plasma and tissue transaminases might represent a normal response to stress for survival.
微粒体甘油三酯转移蛋白（MTP）是降低血浆脂质的靶点，因为它在富含甘油三酯的脂蛋白生物合成中不可或缺。在西方饮食喂养的小鼠中抑制 MTP 可降低血浆甘油三酯/胆固醇，而增加血浆丙氨酸/天冬氨酸转氨酶（ALT/AST）和肝甘油三酯/游离胆固醇。游离胆固醇在内质网（ER）和线粒体中积累，导致 ER 和氧化应激。机制研究表明，MTP 抑制通过上调 IRE1α/cJun 通路增加 GPT/GOT1 基因的转录，从而导致 ALT1/AST1 的合成和释放增加。因此，GPT/GOT1 基因的转录上调是一种主要机制，可响应 ER 应激，提高血浆转氨酶。血浆和组织转氨酶的升高可能代表着生存应激的正常反应。
