From the Endocrinology Centre, William Harvey Research Institute, Queen Mary University of London and Barts and The London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, United Kingdom.
J Biol Chem. 2014 Feb 14;289(7):4244-61. doi: 10.1074/jbc.M113.479980. Epub 2013 Dec 13.
Triglycerides and cholesterol are essential for life in most organisms. Triglycerides serve as the principal energy storage depot and, where vascular systems exist, as a means of energy transport. Cholesterol is essential for the functional integrity of all cellular membrane systems. The endoplasmic reticulum is the site of secretory lipoprotein production and de novo cholesterol synthesis, yet little is known about how these activities are coordinated with each other or with the activity of the COPII machinery, which transports endoplasmic reticulum cargo to the Golgi. The Sar1B component of this machinery is mutated in chylomicron retention disorder, indicating that this Sar1 isoform secures delivery of dietary lipids into the circulation. However, it is not known why some patients with chylomicron retention disorder develop hepatic steatosis, despite impaired intestinal fat malabsorption, and why very severe hypocholesterolemia develops in this condition. Here, we show that Sar1B also promotes hepatic apolipoprotein (apo) B lipoprotein secretion and that this promoting activity is coordinated with the processes regulating apoB expression and the transfer of triglycerides/cholesterol moieties onto this large lipid transport protein. We also show that although Sar1A antagonizes the lipoprotein secretion-promoting activity of Sar1B, both isoforms modulate the expression of genes encoding cholesterol biosynthetic enzymes and the synthesis of cholesterol de novo. These results not only establish that Sar1B promotes the secretion of hepatic lipids but also adds regulation of cholesterol synthesis to Sar1B's repertoire of transport functions.
在大多数生物体中，甘油三酯和胆固醇都是生命所必需的。甘油三酯是主要的能量储存库，在存在血管系统的地方，它是能量运输的一种方式。胆固醇对于所有细胞膜系统的功能完整性都是必不可少的。内质网是分泌性脂蛋白产生和从头胆固醇合成的场所，但对于这些活动如何彼此协调或与将内质网货物运输到高尔基体的 COPII 机制的活动协调，我们知之甚少。这种机制的 Sar1B 成分在乳糜微粒滞留障碍中发生突变，表明这种 Sar1 同工型确保了膳食脂质进入循环。然而，尚不清楚为什么一些乳糜微粒滞留障碍患者尽管存在肠道脂肪吸收不良，但仍会发生肝脂肪变性，以及为什么在这种情况下会出现非常严重的低胆固醇血症。在这里，我们表明 Sar1B 还促进了肝载脂蛋白 (apo) B 脂蛋白的分泌，并且这种促进作用与调节 apoB 表达的过程以及将甘油三酯/胆固醇部分转移到这种大的脂质转运蛋白上相协调。我们还表明，尽管 Sar1A 拮抗 Sar1B 的脂蛋白分泌促进活性，但这两种同工型都调节编码胆固醇生物合成酶的基因的表达以及胆固醇的从头合成。这些结果不仅确立了 Sar1B 促进了肝脏脂质的分泌，而且还增加了 Sar1B 在运输功能中的胆固醇合成的调节作用。
