Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping
Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping
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DOI：
10.1016/j.jhep.2020.03.006
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发表时间：
2020-08-01
影响因子：
25.7
通讯作者：
Liu, Wanqing
中科院分区：
文献类型：
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作者：
Liu, Zhipeng;Zhang, Yang;Liu, Wanqing
背景与目的：非酒精性脂肪性肝病(NAFLD)、2型糖尿病(T2D)和肥胖在流行病学上相互关联，但它们之间的因果关系尚不完全清楚。方法：使用英国生物库和公开的全基因组关联研究数据，进行两样本双向孟德尔随机化分析，检验NAFLD、T2D和肥胖之间的因果关系。以表达人PNPLA3-I148M亚型(TghPNPLA3-I148M)的转基因小鼠为例，验证因果效应，并探索其可能的机制。结果：基因驱动的NAFLD显著增加T2D和中心性肥胖的风险，但不增加胰岛素抵抗或全身性肥胖，而基因驱动的T2D、体重指数和WHRadjBMI原因增加NAFLD的风险。针对PNPLA3的动物研究证实了这些因果效应：与TghPNPLA3-I148I对照组相比，TghPNPLA3-I148M小鼠出现了葡萄糖耐量异常和内脏脂肪增加，但保持了正常的胰岛素敏感性，体重减轻，循环总胆固醇降低。从机制上讲，TghPNPLA3-I148M小鼠表现出胰腺胰岛素减少但胰升糖素分泌增加，这与胰腺炎症增加有关。此外，在TghPNPLA3-I148M小鼠中，肝脏胆固醇生物合成途径基因的转录被显著抑制，而产热途径基因在皮下和棕色脂肪组织中的转录被激活，而在内脏脂肪组织中则不被激活。结论：我们的研究表明，基因驱动的终生NAFLD导致T2D以晚发型1型糖尿病亚型和中心性肥胖的形式发病；而基因驱动的T2D、肥胖和中心性肥胖都会导致NAFLD的风险增加。这种因果关系揭示了先天和后天如何驱动这些疾病的新见解，为疾病亚型提供了新的假说。报告摘要：非酒精性脂肪肝、2型糖尿病和肥胖症在流行病学上相互关联，但它们的因果关系尚不完全清楚。在这里，我们确定了这些疾病之间的因果关系，这表明这些密切相关的疾病中的每一种都应该进一步划分为亚型。这对于这些疾病的准确诊断、预防和治疗具有重要意义。(C)2020年欧洲肝脏研究协会。爱思唯尔出版，版权所有。
Background & Aims: Non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D) and obesity are epidemiologically correlated with each other but the causal inter-relationships between them remain incompletely understood. We aimed to explore the causal relationships between the 3 diseases.Methods: Using both UK Biobank and publicly available genome-wide association study data, we performed a 2-sample bidirectional Mendelian randomization analysis to test the causal interrelationships between NAFLD, T2D, and obesity. Transgenic mice expressing the human PNPLA3-I148M isoforms (TghPNPLA3-I148M) were used as an example to validate causal effects and explore underlying mechanisms.Results: Genetically driven NAFLD significantly increased the risk of T2D and central obesity but not insulin resistance or generalized obesity, while genetically driven T2D, body mass index and WHRadjBMI causally increased NAFLD risk. The animal study focusing on PNPLA3 corroborated these causal effects: compared to the TghPNPLA3-I148I controls, the TghPNPLA3-I148M mice developed glucose intolerance and increased visceral fat, but maintained normal insulin sensitivity, reduced body weight, and decreased circulating total cholesterol. Mechanistically, the TghPNPLA3-I148M mice demonstrated decreased pancreatic insulin but increased glucagon secretion, which was associated with increased pancreatic inflammation. In addition, transcription of hepatic cholesterol biosynthesis pathway genes was significantly suppressed, while transcription of thermogenic pathway genes was activated in subcutaneous and brown adipose tissues but not in visceral fat in TghPNPLA3-I148M mice.Conclusions: Our study suggests that lifelong, genetically driven NAFLD causally promotes T2D with a late-onset type 1-like diabetic subphenotype and central obesity; while genetically driven T2D, obesity, and central obesity all causally increase the risk of NAFLD. This causal relationship revealed new insights into how nature and nurture drive these diseases, providing novel hypotheses for disease subphenotyping.Lay summary: Non-alcoholic fatty liver disease, type 2 diabetes and obesity are epidemiologically correlated with each other, but their causal relationships were incompletely understood. Herein, we identified causal relationships between these conditions, which suggest that each of these closely related diseases should be further stratified into subtypes. This is important for accurate diagnosis, prevention and treatment of these diseases. (c) 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.