Mutations of NRG4 Contribute to the Pathogenesis of Nonalcoholic Fatty Liver Disease and Related Metabolic Disorders
Mutations of NRG4 Contribute to the Pathogenesis of Nonalcoholic Fatty Liver Disease and Related Metabolic Disorders
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NRG4 突变导致非酒精性脂肪肝及相关代谢紊乱的发病机制
DOI：
10.2337/db21-0064
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发表时间：
2021-10-01
期刊：
影响因子：
7.7
通讯作者：
Hu, Cheng
中科院分区：
文献类型：
--
作者：
Li, Yangyang;Jin, Li;Hu, Cheng
中性调节蛋白4(NRG4)是一种脂肪组织富含的内分泌因子，参与脂肪细胞与肝细胞的通讯，在非酒精性脂肪性肝病(NAFLD)中产生有益的代谢效应。我们评估了NRG4在人类中的生理作用，并揭示了NRG4变异在NAFLD和相关代谢紊乱发病机制中的作用。我们通过对224例严重肥胖者进行全外显子组测序和对2388例上海肥胖研究受试者进行外显子组基因分型，在NRG4 EGF样域中发现了两个罕见的错义突变-p.R44H和p.E47Q。高表达动物模型显示野生型(WT)NRG4可减轻高脂饮食诱导的肝脏脂肪生成，改善能量代谢。NRG4 E47Q增强保护作用，而NRG4 R44H失去保护作用。与NRG4 R44H不同，NRG4 E47Q通过ErbB4-STAT5-SREBP-1C途径激活ErbB4的磷酸化，负调控新生脂肪生成。表面等离子体共振实验表明，E47Q NRG4与ErbB4结合的亲和力高于WT，而R44H与ErbB4没有结合。总之，这项研究表明，NRG4的遗传变异可以产生功能异常的突变蛋白，NRG4功能受损或增强可能是NAFLD和相关代谢紊乱的危险因素或保护因素。
Neuregulin 4 (Nrg4), an adipose tissue-enriched endocrine factor, participates in adipocyte-to-hepatocyte communication, eliciting beneficial metabolic effects in nonalcoholic fatty liver disease (NAFLD). We evaluate the physiological roles of NRG4 in humans and unravel the role of NRG4 variants in the pathogenesis of NAFLD and related metabolic disorders. We identified two rare missense mutations-p.R44H and p.E47Q-in the NRG4 EGF-like domain by whole-exome sequencing in 224 severely obese subjects and exome genotyping in 2,388 subjects from the Shanghai Obesity Study. The overexpression animal models showed that wild-type (WT) Nrg4 could attenuate high-fat diet-induced hepatic lipogenesis and improve energy metabolism. Nrg4 E47Q enhanced the protective effect, whereas Nrg4 R44H lost this function. Unlike Nrg4 R44H, Nrg4 E47Q activated the phosphorylation of ErbB4 and negatively regulated de novo lipogenesis through the ErbB4-STAT5-SREBP-1C pathway. The surface plasmon resonance experiments revealed a higher affinity of E47Q Nrg4 than WT to bind ErbB4, while R44H showed no binding. In conclusion, the study suggests that genetic variations in NRG4 could produce mutant proteins with aberrant functions and that impaired or enhanced Nrg4 function could be either a risk factor or a protective factor for NAFLD and associated metabolic disorders.