Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, NSW, Australia.
Virgen del Rocío University Hospital, Institute of Biomedicine of Seville, Sevilla, Spain.
J Hepatol. 2019 Mar;70(3):494-500. doi: 10.1016/j.jhep.2018.10.021. Epub 2018 Oct 31.
BACKGROUND & AIMS: Irisin, the cleaved extra-cellular fragment of the Fibronectin type III domain-containing protein 5 (FNDC5) is a myokine that is proposed to have favorable metabolic activity. We aimed to elucidate the currently undefined role of variants in the FNDC5 gene in non-alcoholic fatty liver disease (NAFLD).
We prioritized single nucleotide polymorphisms in FNDC5 on the basis of their putative biological function and identified rs3480 in the 3' untranslated region (3'UTR). We studied the association of rs3480 with liver disease severity and the metabolic profile of 987 Caucasian patients with NAFLD. Functional investigations were undertaken using luciferase reporter assays of the 3'UTR of human FNDC5, pyrosequencing for allele-specific expression of FNDC5 in liver, measurement of serum irisin, and bioinformatics analysis.
The rs3480 (G) allele was associated with advanced steatosis (OR 1.29; 95% CI 1.08-1.55; p = 0.004), but not with other histological features. This effect was independent but additive to PNPLA3 and TM6SF2. The rs3480 polymorphism influenced FNDC5 mRNA stability and the binding of miR-135a-5P. Compared with controls, hepatic expression of this microRNA was upregulated while FNDC5 expression was downregulated. Elevated serum irisin was associated with reduced steatosis, and an improved metabolic profile.
Carriage of the FNDC5 rs3480 minor (G) allele is associated with more severe steatosis in NAFLD through a microRNA-mediated mechanism controlling FNDC5 mRNA stability. Irisin is likely to have a favorable metabolic impact on NAFLD.
Irisin is a novel protein produced mainly by muscle, which is known to be released into the circulation, with an unclear role in liver fat deposition. This study demonstrates that genetic variants in the gene encoding the irisin protein modulate the risk of liver fat in patients with fatty liver disease. Interestingly, these effects are independent of, but additive to those of other recently described genetic variants that contribute to liver fat. In functional studies, we have deciphered the detailed molecular mechanisms by which this genetic variant mediates its effects.
鸢尾素是纤维连接蛋白 III 型结构域包含蛋白 5（FNDC5）的细胞外片段，被认为具有代谢活性。我们旨在阐明 FNDC5 基因中的变异体在非酒精性脂肪性肝病（NAFLD）中的作用尚不清楚。
我们根据其潜在的生物学功能对 FNDC5 中的单核苷酸多态性进行了优先级排序，并鉴定出 3'非翻译区（3'UTR）中的 rs3480。我们研究了 rs3480 与 987 例白人 NAFLD 患者的肝脏疾病严重程度和代谢特征的相关性。使用人 FNDC5 的 3'UTR 荧光素酶报告基因检测、肝 FNDC5 等位基因特异性表达的焦磷酸测序、血清鸢尾素的测量以及生物信息学分析进行功能研究。
rs3480（G）等位基因与晚期脂肪变性相关（OR 1.29；95%CI 1.08-1.55；p=0.004），但与其他组织学特征无关。这种影响是独立的，但可与 PNPLA3 和 TM6SF2 相加。rs3480 多态性影响 FNDC5 mRNA 的稳定性和 miR-135a-5P 的结合。与对照组相比，该 microRNA 的肝表达上调，而 FNDC5 表达下调。升高的血清鸢尾素与减轻脂肪变性和改善代谢特征有关。
携带 FNDC5 rs3480 次要（G）等位基因与 NAFLD 中更严重的脂肪变性相关，这是通过一种 miRNA 介导的机制控制 FNDC5 mRNA 稳定性引起的。鸢尾素可能对 NAFLD 具有有利的代谢影响。
鸢尾素是一种主要由肌肉产生的新型蛋白，已知其被释放到循环中，但其在肝脂肪沉积中的作用尚不清楚。本研究表明，编码鸢尾素蛋白的基因中的遗传变异体调节了脂肪性肝病患者的肝脏脂肪沉积风险。有趣的是，这些影响是独立的，但可与最近描述的其他遗传变异体的影响相加，这些变异体有助于肝脏脂肪。在功能研究中，我们已经破译了该遗传变异体介导其作用的详细分子机制。
