Hess Anne Lundby, Carayol Jérôme, Blædel Trine, Hager Jörg, Di Cara Alessandro, Astrup Arne, Saris Wim H M, Larsen Lesli Hingstrup, Valsesia Armand
1The Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Rolighedsvej 26, 1958 Frederiksberg C, Denmark.
Nestlé Institute of Health Sciences, Lausanne, Switzerland.
Genes Nutr. 2018 Apr 2;13:7. doi: 10.1186/s12263-018-0597-3. eCollection 2018.
Angiopoietin-like protein 3 (ANGPTL3), a liver-derived protein, plays an important role in the lipid and lipoprotein metabolism. Using data available from the DiOGenes study, we assessed the link with clinical improvements (weight, plasma lipid, and insulin levels) and changes in liver markers, alanine aminotransferase, aspartate aminotransferase (AST), adiponectin, fetuin A and B, and cytokeratin 18 (CK-18), upon low-calorie diet (LCD) intervention. We also examined the role of genetic variation in determining the level of circulating ANGPTL3 and the relation between the identified genetic markers and markers of hepatic steatosis.
DiOGenes is a multicenter, controlled dietary intervention where obese participants followed an 8-week LCD (800 kcal/day, using a meal replacement product). Plasma ANGPTL3 and liver markers were measured using the SomaLogic (Boulder, CO) platform. Protein quantitative trait locus (pQTL) analyses assessed the link between more than four million common variants and the level of circulating ANGPTL3 at baseline and changes in levels during the LCD intervention.
Changes in ANGPTL3 during weight loss showed only marginal association with changes in triglycerides (nominal = 0.02) and insulin ( = 0.04); these results did not remain significant after correcting for multiple testing. However, significant association (after multiple-testing correction) were observed between changes in ANGPTL3 and AST during weight loss ( = 0.004) and between ANGPTL3 and CK-18 (baseline = 1.03 × 10, during weight loss = 1.47 × 10). Our pQTL study identified two loci significantly associated with changes in ANGPTL3. One of these loci (the -- gene cluster) also displayed significant association with changes in CK-18 levels during weight loss ( = 0.007).
We clarify the link between circulating levels of ANGPTL3 and specific markers of liver function. We demonstrate that changes in ANGPLT3 and CK-18 during LCD are under genetic control from -acting variants. Our results suggest an extended function of ANGPTL3 in the inflammatory state of liver steatosis and toward liver metabolic processes.
血管生成素样蛋白3（ANGPTL3）是一种肝脏来源的蛋白质，在脂质和脂蛋白代谢中起重要作用。利用来自DiOGenes研究的数据，我们评估了低热量饮食（LCD）干预后，ANGPTL3与临床改善情况（体重、血脂和胰岛素水平）以及肝脏标志物、丙氨酸转氨酶、天冬氨酸转氨酶（AST）、脂联素、胎球蛋白A和B以及细胞角蛋白18（CK-18）变化之间的联系。我们还研究了基因变异在决定循环ANGPTL3水平中的作用，以及所确定的基因标记与肝脂肪变性标记之间的关系。
DiOGenes是一项多中心对照饮食干预研究，肥胖参与者采用代餐产品进行为期8周的LCD（800千卡/天）。使用SomaLogic（科罗拉多州博尔德）平台测量血浆ANGPTL3和肝脏标志物。蛋白质定量性状位点（pQTL）分析评估了超过400万个常见变异与基线时循环ANGPTL3水平以及LCD干预期间水平变化之间的联系。
体重减轻期间ANGPTL3的变化与甘油三酯变化（名义值=0.02）和胰岛素变化（=0.04）仅显示出微弱关联；在进行多重检验校正后，这些结果不再显著。然而，在体重减轻期间观察到ANGPTL3变化与AST之间存在显著关联（多重检验校正后，=0.004），以及ANGPTL3与CK-18之间存在显著关联（基线时=1.03×10，体重减轻期间=1.47×10）。我们的pQTL研究确定了两个与ANGPTL3变化显著相关的基因座。其中一个基因座（--基因簇）在体重减轻期间也与CK-18水平变化显示出显著关联（=0.007）。
我们阐明了循环ANGPTL3水平与肝功能特定标志物之间的联系。我们证明，LCD期间ANGPLT3和CK-18的变化受来自-作用变异的基因控制。我们的结果表明ANGPTL3在肝脂肪变性炎症状态及肝脏代谢过程中具有扩展功能。
