关键词: Cardiometabolic disease Circulating Mfge8 Exosomes Rare variants Zebrafish

Mesh : Humans Diabetes Mellitus, Type 2 / genetics blood Cardiovascular Diseases / genetics blood Zebrafish / genetics Animals Male Female Middle Aged Asian People / genetics Exosomes / genetics metabolism Mutation, Missense Adult Genetic Predisposition to Disease Blood Glucose / metabolism Aged Polymorphism, Single Nucleotide

来  源:   DOI:10.1016/j.gene.2024.148712

Abstract:
MFGE8 is a major exosome (EV) protein known to mediate inflammation and atherosclerosis in type 2 diabetes mellitus (T2DM) in animal studies. The pathophysiological role of this protein in obesity, T2DM, and cardiovascular disease is less investigated in humans. Earlier we reported a rare Asian Indian population-specific missense variant (rs371227978; Arg148His) in the MFGE8 gene associated with increased circulating Mfge8 and T2DM. We have further investigated the role of Mfge8 with T2DM risk in additional Asian Indians (n = 4897) and Europeans and other multiethnic cohorts from UK Biobank (UKBB) (n = 455,808) and the US (n = 1150). We also evaluated the exposure of Mfge8-enriched human EVs in zebrafish (ZF) for their impact on cardiometabolic organ system. Most individual carriers of Arg148His variant not only had high circulating Mfge8 but also revealed a positive significant correlation with glucose (r = 0.42; p = 4.9 × 10-04), while the non-carriers showed a negative correlation of Mfge8 with glucose (r = -0.38; p = 0.001) in Asian Indians. The same variant was monomorphic in non-South Asian ethnicities. Even without the variant, serum Mfge8 correlated significantly with blood glucose in other non-South Asian ethnicities (r = 0.47; p = 2.2 × 10-13). Since Mfge8 is an EV marker, we tested the exposure of Mfge8-enriched human EVs to ZF larvae as an exploratory study. The ZF larvae showed rapid effects on insulin-sensitive organs, developing fatty liver disease, heart hypertrophy and exhibiting redundant growth with poor muscular architecture with and without the high-fat diet (HFD). In contrast, the control group fishes developed fatty liver disease and heart hypertrophy only after the HFD feeding. Backed with strong support from animal studies on the role of Mfge8 in obesity, insulin resistance, and atherosclerosis, the current research suggests that circulating Mfge8 may become a potential marker for predicting the risk of T2DM and cardiovascular disease in humans.
摘要:
MFGE8是一种主要的外泌体(EV)蛋白,在动物研究中已知可介导2型糖尿病(T2DM)中的炎症和动脉粥样硬化。该蛋白在肥胖中的病理生理作用,T2DM,心血管疾病在人类中的研究较少。早些时候,我们报道了MFGE8基因中罕见的亚裔印度人口特异性错义变体(rs371227978;Arg148His),该基因与循环Mfge8和T2DM增加有关。我们进一步研究了Mfge8在其他亚洲印第安人(n=4897),欧洲人和其他来自英国生物银行(UKBB)(n=455,808)和美国(n=1150)的多种族队列中与T2DM风险的作用。我们还评估了斑马鱼(ZF)中富含Mfge8的人类EV对心脏代谢器官系统的影响。Arg148His变异体的大多数个体携带者不仅具有高循环Mfge8,而且与葡萄糖呈正相关(r=0.42;p=4.9×10-04),而在亚洲印第安人中,非携带者显示Mfge8与葡萄糖呈负相关(r=-0.38;p=0.001)。在非南亚种族中,相同的变体是单态的。即使没有变体,在其他非南亚种族中,血清Mfge8与血糖显着相关(r=0.47;p=2.2×10-13)。由于Mfge8是EV标记,作为一项探索性研究,我们测试了富含Mfge8的人类电动汽车对ZF幼虫的暴露情况。ZF幼虫对胰岛素敏感器官表现出快速作用,发展为脂肪肝疾病,有或没有高脂饮食(HFD)的情况下,心脏肥大并表现出多余的生长,肌肉结构较差。相比之下,对照组鱼仅在HFD喂养后才出现脂肪肝和心脏肥大。动物研究支持Mfge8在肥胖中的作用,胰岛素抵抗,和动脉粥样硬化,目前的研究表明,循环Mfge8可能成为预测人类T2DM和心血管疾病风险的潜在标志物.
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