Department of Pediatrics, University "La Sapienza", Rome, Italy.
Research Unit of Molecular Genetics of Complex Phenotypes, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy.
Pediatr Res. 2018 Nov;84(5):696-703. doi: 10.1038/s41390-018-0132-7. Epub 2018 Aug 4.
FADS1 gene encodes delta 5 desaturase, a rate-limiting enzyme in the metabolism of n-3 and n-6 polyunsaturated fatty acids (PUFAs). Minor alleles of FADS1 locus polymorphisms are associated with reduced FADS1 expression and intra-hepatic fat accumulation. However, the relationship between FADS1 expression and pediatric nonalcoholic fatty liver disease (NAFLD) risk remains to be explored.
We analyzed FADS1 transcription levels and their association with intra-hepatic fat and histology in children, and we performed pathway enrichment analysis on transcriptomic profiles associated with FADS1 polymorphisms. We also evaluated the weight of FADS1 alleles on the response to combined docosahexaenoic acid, choline, and vitamin E (DHA-CHO-VE) treatment.
FADS1 mRNA level was significantly and inversely associated with intra-hepatic fat (p = 0.004), degree of steatosis (p = 0.03), fibrosis (p = 0.05), and NASH (p = 0.008) among pediatric livers. Transcriptomics demonstrated a significant enrichment of a number of pathways strongly related to NAFLD (e.g., liver damage, fibrosis, and hepatic stellate cell activation). Compared to children who are common allele homozygotes, children with FADS1 minor alleles had a greater reduction in steatosis, fibrosis, and NAFLD activity score after DHA-CHO-VE.
This study suggests that decreased FADS1 expression may be associated with NAFLD in children but an increased response to DHA-CHO-VE.
FADS1 基因编码 delta 5 去饱和酶，这是 n-3 和 n-6 多不饱和脂肪酸（PUFA）代谢中的限速酶。FADS1 基因座多态性的次要等位基因与 FADS1 表达降低和肝内脂肪堆积有关。然而，FADS1 表达与儿童非酒精性脂肪性肝病（NAFLD）风险之间的关系仍有待探讨。
我们分析了儿童 FADS1 转录水平及其与肝内脂肪和组织学的关系，并对与 FADS1 多态性相关的转录组谱进行了途径富集分析。我们还评估了 FADS1 等位基因对联合二十二碳六烯酸、胆碱和维生素 E（DHA-CHO-VE）治疗反应的影响。
FADS1 mRNA 水平与儿童肝内脂肪（p=0.004）、脂肪变性程度（p=0.03）、纤维化（p=0.05）和 NASH（p=0.008）呈显著负相关。转录组学显示，与 NAFLD 强烈相关的许多途径显著富集（例如，肝损伤、纤维化和肝星状细胞激活）。与常见等位基因纯合子的儿童相比，FADS1 次要等位基因的儿童在接受 DHA-CHO-VE 治疗后，脂肪变性、纤维化和 NAFLD 活动评分的降低更为显著。
本研究表明，FADS1 表达降低可能与儿童的 NAFLD 有关，但对 DHA-CHO-VE 的反应增强。
