Lipid Absorption Defects in Intestine-specific Microsomal Triglyceride Transfer Protein and ATP-binding Cassette Transporter A1-deficient Mice
Lipid Absorption Defects in Intestine-specific Microsomal Triglyceride Transfer Protein and ATP-binding Cassette Transporter A1-deficient Mice
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DOI：
10.1074/jbc.m113.501247
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发表时间：
2013-10-18
影响因子：
4.8
通讯作者：
Hussain, M. Mahmood
中科院分区：
文献类型：
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作者：
Iqbal, Jahangir;Parks, John S.;Hussain, M. Mahmood
我们之前描述了载脂蛋白 B (apoB) 依赖性和非依赖性胆固醇吸收途径以及微粒体甘油三酯转运蛋白 (MTP) 和 ATP 结合盒转运蛋白 A1 (ABCA1) 在这些途径中的作用。为了评估这些途径对胆固醇吸收的贡献并确定是否存在其他途径，我们培育了肠道中单独或组合缺乏 MTP 和 ABCA1 的小鼠。 Mttp 和 Abca1 的肠道缺失使血浆胆固醇浓度分别降低 45% 和 24%，而它们的联合缺失则使血浆胆固醇浓度降低 59%。在没有ABCA1的情况下，急性胆固醇吸收减少了28%，当在肠道中单独删除MTP或与ABCA1一起删除MTP时，急性胆固醇吸收减少了92-95%。 MTP 缺乏显着降低甘油三酯的吸收，但 ABCA1 缺乏没有影响。 ABCA1 缺乏不会影响细胞脂质，但 Mttp 缺乏会显着增加肠道甘油三酯和游离脂肪酸水平。当小鼠肠道 ABCA1 也缺乏时，Mttp 缺陷肠道中肠道游离脂肪酸（而非甘油三酯）的积累被阻止。由于过氧化物酶体增殖物激活受体 (PPAR) 和肉碱棕榈酰转移酶 1 (CPT1) 表达增加，这些基因的联合缺陷增加了肠道脂肪酸氧化。这些研究表明肠道 MTP 和 ABCA1 对于脂质吸收至关重要，是血浆和肠道脂质水平的主要决定因素。减少它们的活性可能会降低血浆脂质浓度。
We have previously described apolipoprotein B (apoB)-dependent and -independent cholesterol absorption pathways and the role of microsomal triglyceride transfer protein (MTP) and ATP-binding cassette transporter A1 (ABCA1) in these pathways. To assess the contribution of these pathways to cholesterol absorption and to determine whether there are other pathways, we generated mice that lack MTP and ABCA1, individually and in combination, in the intestine. Intestinal deletions of Mttp and Abca1 decreased plasma cholesterol concentrations by 45 and 24%, respectively, whereas their combined deletion reduced it by 59%. Acute cholesterol absorption was reduced by 28% in the absence of ABCA1, and it was reduced by 92-95% when MTP was deleted in the intestine alone or together with ABCA1. MTP deficiency significantly reduced triglyceride absorption, although ABCA1 deficiency had no effect. ABCA1 deficiency did not affect cellular lipids, but Mttp deficiency significantly increased intestinal levels of triglycerides and free fatty acids. Accumulation of intestinal free fatty acids, but not triglycerides, in Mttp-deficient intestines was prevented when mice were also deficient in intestinal ABCA1. Combined deficiency of these genes increased intestinal fatty acid oxidation as a consequence of increased expression of peroxisome proliferator-activated receptor- (PPAR) and carnitine palmitoyltransferase 1 (CPT1). These studies show that intestinal MTP and ABCA1 are critical for lipid absorption and are the main determinants of plasma and intestinal lipid levels. Reducing their activities might lower plasma lipid concentrations.