de Vogel-van den Bosch Heleen M, de Wit Nicole J W, Hooiveld Guido J E J, Vermeulen Hanneke, van der Veen Jelske N, Houten Sander M, Kuipers Folkert, Müller Michael, van der Meer Roelof
Nutrition, Metabolism and Genomics Group, Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands.
Am J Physiol Gastrointest Liver Physiol. 2008 May;294(5):G1171-80. doi: 10.1152/ajpgi.00360.2007. Epub 2008 Mar 20.
Transporters present in the epithelium of the small intestine determine the efficiency by which dietary and biliary cholesterol are taken up into the body and thus control whole-body cholesterol balance. Niemann-Pick C1 Like Protein 1 (Npc1l1) transports cholesterol into the enterocyte, whereas ATP-binding cassette transporters Abca1 and Abcg5/Abcg8 are presumed to be involved in cholesterol efflux from the enterocyte toward plasma HDL and back into the intestinal lumen, respectively. Abca1, Abcg5, and Abcg8 are well-established liver X receptor (LXR) target genes. We examined the effects of a high-fat diet on expression and function of cholesterol transporters in the small intestine in mice. Npc1l1, Abca1, Abcg5, and Abcg8 were all downregulated after 2, 4, and 8 wk on a cholesterol-free, high-fat diet. The high-fat diet did not affect biliary cholesterol secretion but diminished fractional cholesterol absorption from 61 to 42% (P < 0.05). In an acute experiment in which triacylglycerols of unsaturated fatty acids were given by gavage, we found that this downregulation occurs within a 6-h time frame. Studies in LXRalpha-null mice, confirmed by in vitro data, showed that fatty acid-induced downregulation of cholesterol transporters is LXRalpha independent and associated with a posttranslational increase in 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity that reflects induction of cholesterol biosynthesis as well as with a doubling of neutral fecal sterol loss. This study highlights the induction of adaptive changes in small intestinal cholesterol metabolism during exposure to dietary fat.
存在于小肠上皮中的转运蛋白决定了膳食和胆汁胆固醇被吸收进入体内的效率，从而控制全身胆固醇平衡。尼曼-皮克C1样蛋白1（Npc1l1）将胆固醇转运到肠细胞中，而ATP结合盒转运蛋白Abca1和Abcg5/Abcg8分别被认为参与胆固醇从肠细胞向血浆高密度脂蛋白的流出以及回流到肠腔中。Abca1、Abcg5和Abcg8是公认的肝脏X受体（LXR）靶基因。我们研究了高脂饮食对小鼠小肠中胆固醇转运蛋白表达和功能的影响。在无胆固醇的高脂饮食喂养2、4和8周后，Npc1l1、Abca1、Abcg5和Abcg8均下调。高脂饮食不影响胆汁胆固醇分泌，但使胆固醇分数吸收率从61%降至42%（P<0.05）。在一项急性实验中，通过灌胃给予不饱和脂肪酸的三酰甘油，我们发现这种下调在6小时内发生。在LXRα基因敲除小鼠中的研究以及体外数据证实，脂肪酸诱导的胆固醇转运蛋白下调不依赖LXRα，并且与3-羟基-3-甲基戊二酰辅酶A还原酶活性的翻译后增加有关，这反映了胆固醇生物合成的诱导以及中性粪便固醇损失增加一倍。这项研究强调了在暴露于膳食脂肪期间小肠胆固醇代谢中适应性变化的诱导。
