Chen Zhouji, Newberry Elizabeth P, Norris Jin Y, Xie Yan, Luo Jianyang, Kennedy Susan M, Davidson Nicholas O
Center for Human Nutrition, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
J Lipid Res. 2008 Sep;49(9):2013-22. doi: 10.1194/jlr.M800240-JLR200. Epub 2008 Jun 2.
Microsomal triglyceride transfer protein (Mttp) is a key player in the assembly and secretion of hepatic very low density lipoproteins (VLDL). Here we determined the effects of Mttp overexpression on hepatic triglyceride (TG) and VLDL secretion in leptin-deficient (ob/ob) mice, specifically in relation to apolipoproteinB (apoB) isoforms. We crossed Apobec1(-/-) mice with congenic ob/ob mice to generate apoB100-only ob/ob mice (A-ob/ob). The obesity phenotype in both genotypes was similar, but A-ob/ob mice had greater hepatic TG content. Administration of recombinant adenovirus expressing murine Mttp cDNA (Ad-mMTP) increased hepatic Mttp content and activity and increased hepatic VLDL-TG secretion in A-ob/ob mice. However, despite equivalent overexpression of Mttp, there was no change in VLDL-TG secretion in ob/ob mice in a wild-type Apobec1 background. Metabolic labeling studies in primary hepatocytes from A-ob/ob mice demonstrated that Ad-mMTP increased triglyceride secretion without changing the synthesis and secretion of apoB100, suggesting greater incorporation of TG into existing VLDL particles rather than increased particle number. Ad-mMTP administration failed to increase hepatic VLDL secretion in lean Apobec1(-/-) mice or controls. By contrast, VLDL secretion increased and hepatic TG content decreased following Ad-mMTP administration to human APOB transgenic mice crossed into the Apobec1(-/-) line. These findings demonstrate that Ad-mMTP increases murine hepatic VLDL-TG secretion only in the apoB100 background, and even then only in situations with either increased hepatic TG accumulation or increased apoB100 expression.
微粒体甘油三酯转运蛋白（Mttp）是肝脏极低密度脂蛋白（VLDL）组装和分泌过程中的关键因子。在此，我们确定了Mttp过表达对瘦素缺乏（ob/ob）小鼠肝脏甘油三酯（TG）和VLDL分泌的影响，特别是与载脂蛋白B（apoB）异构体的关系。我们将载脂蛋白B mRNA编辑酶催化多肽样蛋白1（Apobec1）基因敲除小鼠与同基因ob/ob小鼠杂交，以产生仅表达apoB100的ob/ob小鼠（A-ob/ob）。两种基因型的肥胖表型相似，但A-ob/ob小鼠的肝脏TG含量更高。给予表达小鼠Mttp cDNA的重组腺病毒（Ad-mMTP）可增加A-ob/ob小鼠肝脏Mttp的含量和活性，并增加肝脏VLDL-TG的分泌。然而，尽管Mttp的过表达程度相当，但在野生型Apobec1背景下的ob/ob小鼠中，VLDL-TG的分泌没有变化。对A-ob/ob小鼠原代肝细胞进行的代谢标记研究表明，Ad-mMTP增加了甘油三酯的分泌，但没有改变apoB100的合成和分泌，这表明更多的TG被整合到现有的VLDL颗粒中，而不是增加颗粒数量。给瘦的Apobec1基因敲除小鼠或对照小鼠注射Ad-mMTP未能增加肝脏VLDL的分泌。相比之下，给转入Apobec1基因敲除品系的人APOB转基因小鼠注射Ad-mMTP后，VLDL分泌增加，肝脏TG含量降低。这些发现表明，Ad-mMTP仅在apoB100背景下增加小鼠肝脏VLDL-TG的分泌，即便如此，也仅在肝脏TG积累增加或apoB100表达增加的情况下才会发生。
