Cross-tissue omics analysis discovers ten adipose genes encoding secreted proteins in obesity-related non-alcoholic fatty liver disease.
Cross-tissue omics analysis discovers ten adipose genes encoding secreted proteins in obesity-related non-alcoholic fatty liver disease.
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DOI：
10.1016/j.ebiom.2023.104620
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发表时间：
2023-06
期刊：
影响因子：
11.1
通讯作者：
Pajukanta, Paivi
中科院分区：
文献类型：
--
作者：
Darci-Maher, Nicholas;Alvarez, Marcus;Arasu, Uma Thanigai;Selvarajan, Ilakya;Lee, Seung Hyuk T.;Pan, David Z.;Miao, Zong;Das, Sankha Subhra;Kaminska, Dorota;Ord, Tiit;Benhammou, Jihane N.;Wabitsch, Martin;Pisegna, Joseph R.;Mannisto, Ville;Pietilainen, Kirsi H.;Laakso, Markku;Sinsheimer, Janet S.;Kaikkonen, Minna U.;Pihlajamaki, Jussi;Pajukanta, Paivi
关键词：
非酒精性脂肪性肝病（NAFLD）是一种快速增长、诊断率低的流行病。我们假设与肥胖相关的炎症损害了脂肪组织的功能，阻碍了有效的脂肪储存，从而促使异位脂肪在肝脏中堆积。
为了确定基于脂肪的机制以及非酒精性脂肪性肝病的潜在血清生物标志物候选物（SBCs），我们利用来自肥胖个体队列中同一人的脂肪组织和肝脏的双组织RNA测序（RNA - seq）数据，并结合基于组织学的非酒精性脂肪性肝病诊断结果。我们首先在肥胖个体的皮下脂肪组织中（而非肝脏中）筛选出在非酒精性脂肪性肝病中差异表达（DE）的基因；这些基因编码分泌到血清中的蛋白质，并且在脂肪组织中优先表达。然后通过最佳子集分析、人前脂肪细胞分化过程中的基因敲低实验、人肝HepG2细胞中的重组蛋白处理实验以及遗传分析，将所确定的基因筛选为关键的源于脂肪的非酒精性脂肪性肝病基因。
我们发现了一组基因，包括10个SBCs，它们可能通过影响脂肪组织功能来调节非酒精性脂肪性肝病的发病机制。基于最佳子集分析，我们进一步对两个人体脂肪细胞中的SBCs——CCDC80和SOD3进行基因敲低以及后续的分化实验，结果表明它们调节关键的脂肪生成基因，如LPL、SREBPF1和LEP。我们还表明，用CCDC80和SOD3重组蛋白处理肝HepG2细胞会影响与脂肪变性和脂质代谢相关的基因，包括PPARA、NFE2L2和RNF128。最后，利用在广泛的全基因组关联研究（GWASs）中与血清甘油三酯（TGs）相关的脂肪非酒精性脂肪性肝病差异表达基因的顺式调控变异，我们通过孟德尔随机化（MR）分析证明了血清TGs对非酒精性脂肪性肝病的单向作用。我们还证明了一个调控其中一个SBC基因的单核苷酸多态性（SNP）——rs2845885，其本身就产生了显著的MR结果。这支持了以下结论：非酒精性脂肪性肝病差异表达基因的遗传调控脂肪表达可能通过血清TG水平的变化导致非酒精性脂肪性肝病。
我们的双组织转录组学筛选结果通过提供一组有针对性的10个脂肪组织活性基因作为目前诊断率极低的脂肪性肝病的新血清生物标志物候选物，增进了对与肥胖相关的非酒精性脂肪性肝病的理解。
这项工作得到了R01HG010505和R01DK132775两项基金的支持。基因型 - 组织表达（GTEx）项目得到了美国国立卫生研究院（NIH）共同基金以及美国国立医学图书馆（NLM）、美国国立癌症研究所（NCI）、美国国立心肺血液研究所（NHLBI）、美国国立人类基因组研究所（NHGRI）、美国国立环境卫生科学研究所（NIEHS）和美国国立药物滥用研究所（NIDA）的支持。KOBS研究（J. P.）得到了芬兰科学院（Academy of Finland）、芬兰技术研究中心（VTT）项目基金（EVO/VTR基金2005 - 2019）以及芬兰商业、经济和就业部（Ministry of Employment and the Economy）基金（合同编号138006）的支持。本研究由欧盟（EU）在2020年研究与创新计划下资助（授予M. U. K.的编号为802825的基金）。K. H. P.得到了挪威研究理事会（Research Council of Norway）（基金编号272376、266286、314383和335443）、挪威癌症协会（Cancer Society of Norway）、挪威糖尿病协会（Diabetes Association of Norway）、丹麦独立研究基金（Independent Research Fund Denmark）（基金编号NNF10OC1013354、NNF17OC0027232和NNF20OC0060547）、瑞典研究理事会（Swedish Research Council）、瑞典癌症协会（Cancer Society of Sweden）和瑞典医学研究协会（Swedish Society for Medical Research）基金的资助。I. S.得到了美国国立卫生研究院（NIH）的资助。U. T. A.收到了来自美国国立卫生研究院（NIH）、美国国立医学图书馆（NLM）和美国国立癌症研究所（NCI）的个人基金。
Non-alcoholic fatty liver disease (NAFLD) is a fast-growing, underdiagnosed, epidemic. We hypothesise that obesity-related inflammation compromises adipose tissue functions, preventing efficient fat storage, and thus driving ectopic fat accumulation into the liver. To identify adipose-based mechanisms and potential serum biomarker candidates (SBCs) for NAFLD, we utilise dual-tissue RNA-sequencing (RNA-seq) data in adipose tissue and liver, paired with histology-based NAFLD diagnosis, from the same individuals in a cohort of obese individuals. We first scan for genes that are differentially expressed (DE) for NAFLD in obese individuals’ subcutaneous adipose tissue but not in their liver; encode proteins secreted to serum; and show preferential adipose expression. Then the identified genes are filtered to key adipose-origin NAFLD genes by best subset analysis, knockdown experiments during human preadipocyte differentiation, recombinant protein treatment experiments in human liver HepG2 cells, and genetic analysis. We discover a set of genes, including 10 SBCs, that may modulate NAFLD pathogenesis by impacting adipose tissue function. Based on best subset analysis, we further follow-up on two SBCs CCDC80 and SOD3 by knockdown in human preadipocytes and subsequent differentiation experiments, which show that they modulate crucial adipogenesis genes, LPL, SREBPF1, and LEP. We also show that treatment of the liver HepG2 cells with the CCDC80 and SOD3 recombinant proteins impacts genes related to steatosis and lipid processing, including PPARA, NFE2L2, and RNF128. Finally, utilizing the adipose NAFLD DE gene cis-regulatory variants associated with serum triglycerides (TGs) in extensive genome-wide association studies (GWASs), we demonstrate a unidirectional effect of serum TGs on NAFLD with Mendelian Randomization (MR) analysis. We also demonstrate that a single SNP regulating one of the SBC genes, rs2845885, produces a significant MR result by itself. This supports the conclusion that genetically regulated adipose expression of the NAFLD DE genes may contribute to NAFLD through changes in serum TG levels. Our results from the dual-tissue transcriptomics screening improve the understanding of obesity-related NAFLD by providing a targeted set of 10 adipose tissue-active genes as new serum biomarker candidates for the currently grossly underdiagnosed fatty liver disease. The work was supported by grants R01HG010505 and R01DK132775. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the of the , and by , , , , , and . The KOBS study (J. P.) was supported by the , Project grant (EVO/VTR grants 2005–2019), and the grant (Contract no. 138006). This study was funded by the under the 2020 research and innovation program (Grant No. 802825 to M. U. K.). K. H. P. was funded by the (grant numbers 272376, 266286, 314383, and 335443), the , , (grant numbers NNF10OC1013354, NNF17OC0027232, and NNF20OC0060547), , , , and Funds. I. S. was funded by the . Personal grants to U. T. A. were received from the , and the .
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
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64.8
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影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
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影响因子：
5.1
作者：
Cui, R.;Gao, M.;Qu, S.;Liu, D.
通讯作者：
Liu, D.
DOI：
10.1002/hep.31995
发表时间：
2021-11
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Kozumi K;Kodama T;Murai H;Sakane S;Govaere O;Cockell S;Motooka D;Kakita N;Yamada Y;Kondo Y;Tahata Y;Yamada R;Hikita H;Sakamori R;Kamada Y;Daly AK;Anstee QM;Tatsumi T;Morii E;Takehara T
通讯作者：
Takehara T