Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland.
Cell Metab. 2013 Jun 4;17(6):916-928. doi: 10.1016/j.cmet.2013.04.007.
We identified a mutation in the Diet1 gene in a mouse strain that is resistant to hyperlipidemia and atherosclerosis. Diet1 encodes a 236 kD protein consisting of tandem low-density lipoprotein receptor and MAM (meprin-A5-protein tyrosine phosphatase mu) domains and is expressed in the enterocytes of the small intestine. Diet1-deficient mice exhibited an elevated bile acid pool size and impaired feedback regulation of hepatic Cyp7a1, which encodes the rate-limiting enzyme in bile acid synthesis. In mouse intestine and in cultured human intestinal cells, Diet1 expression levels influenced the production of fibroblast growth factor 15/19 (FGF15/19), a hormone that signals from the intestine to liver to regulate Cyp7a1. Transgenic expression of Diet1, or adenoviral-mediated Fgf15 expression, restored normal Cyp7a1 regulation in Diet-1-deficient mice. Diet1 and FGF19 proteins exhibited overlapping subcellular localization in cultured intestinal cells. These results establish Diet1 as a control point in enterohepatic bile acid signaling and lipid homeostasis.
我们在一种对高血脂和动脉粥样硬化有抗性的小鼠品系中鉴定出了 Diet1 基因的突变。Diet1 编码一种 236kD 的蛋白，由串联的低密度脂蛋白受体和 MAM（金属基质蛋白酶 A5-蛋白酪氨酸磷酸酶 μ）结构域组成，在小肠的肠细胞中表达。Diet1 缺陷型小鼠表现出胆汁酸库大小升高和肝 Cyp7a1 的反馈调节受损，后者编码胆汁酸合成的限速酶。在小鼠肠道和培养的人肠道细胞中，Diet1 的表达水平影响成纤维细胞生长因子 15/19（FGF15/19）的产生，这种激素从肠道向肝脏发出信号，调节 Cyp7a1。Diet1 的转基因表达或腺病毒介导的 Fgf15 表达，恢复了 Diet-1 缺陷型小鼠中 Cyp7a1 的正常调节。Diet1 和 FGF19 蛋白在培养的肠道细胞中表现出重叠的亚细胞定位。这些结果确立了 Diet1 作为肠肝胆汁酸信号和脂质稳态的控制点。
