Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker
Liver transcriptomics highlights interleukin-32 as novel NAFLD-related cytokine and candidate biomarker
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DOI：
10.1136/gutjnl-2019-319226
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发表时间：
2020-10-01
期刊：
影响因子：
24.5
通讯作者：
Valenti, Luca
中科院分区：
文献类型：
--
作者：
Baselli, Guido Alessandro;Dongiovanni, Paola;Valenti, Luca
目的非酒精性脂肪性肝病（NAFLD）的发病机制尚不清楚，且缺乏准确的非侵入性生物标志物，这限制了NAFLD的治疗。本研究的目的是通过对存在PNPLA 3 I148 M遗传风险变异的患者进行肝脏转录组学分析来确定新的NAFLD治疗靶点和生物标志物。我们对125名肥胖者的肝脏转录组进行了测序。“重度NAFLD”定义为存在脂肪性肝炎、NAFLD活动性评分>= 4或纤维化分期>= 2。通过ELISA测量最上调的转录物白细胞介素-32（IL 32）的循环水平。结果PNPLA 3 I148 M变异体的携带与肝脏转录组变异的两个主要组成部分相关，并广泛影响基因表达。在重度NAFLD患者中，炎症和脂质代谢途径上调。IL 32是严重NAFLD组中上调最强烈的基因（校正p= 1x 10（-6）），其表达与脂肪变性的严重程度相关，在I148 M变异携带者和非携带者中均是如此。在77例重度肥胖患者中，以及在肝病服务机构评估的160例重复队列中，循环IL 32水平与NAFLD和重度NAFLD相关，与转氨酶无关（p
Objective Efforts to manage non-alcoholic fatty liver disease (NAFLD) are limited by the incomplete understanding of the pathogenic mechanisms and the absence of accurate non-invasive biomarkers. The aim of this study was to identify novel NAFLD therapeutic targets andbiomarkers by conducting liver transcriptomic analysis in patients stratified by the presence of thePNPLA3I148M genetic risk variant. Design We sequenced the hepatic transcriptome of 125 obese individuals. 'Severe NAFLD' was defined as the presence of steatohepatitis, NAFLD activity score >= 4 or fibrosis stage >= 2. The circulating levels of the most upregulated transcript, interleukin-32 (IL32), were measured by ELISA. Results Carriage of thePNPLA3I148M variant correlated with the two major components of hepatic transcriptome variability and broadly influenced gene expression. In patients with severe NAFLD, there was an upregulation of inflammatory and lipid metabolism pathways. IL32 was the most robustly upregulated gene in the severe NAFLD group (adjusted p=1x10(-6)), and its expression correlated with steatosis severity, both in I148M variant carriers and non-carriers. In 77 severely obese, and in a replication cohort of 160 individuals evaluated at the hepatology service, circulating IL32 levels were associated with both NAFLD and severe NAFLD independently of aminotransferases (p