Abstract：
BACKGROUND: Abdominal obesity increases the risk for non-alcoholic fatty liver disease (NAFLD), now known as metabolic dysfunction-associated steatotic liver disease (MASLD).
METHODS: To elucidate the directional cell-type level biological mechanisms underlying the association between abdominal obesity and MASLD, we integrated adipose and liver single nucleus RNA-sequencing and bulk cis-expression quantitative trait locus (eQTL) data with the UK Biobank genome-wide association study (GWAS) data using colocalization. Then we used colocalized cis-eQTL variants as instrumental variables in Mendelian randomization (MR) analyses, followed by functional validation experiments on the target genes of the cis-eQTL variants.
RESULTS: We identified 17 colocalized abdominal obesity GWAS variants, regulating 17 adipose cell-type marker genes. Incorporating these 17 variants into MR discovers a putative tissue-of-origin, cell-type-aware causal effect of abdominal obesity on MASLD consistently with multiple MR methods without significant evidence for pleiotropy or heterogeneity. Single cell data confirm the adipocyte-enriched mean expression of the 17 genes. Our cellular experiments across human adipogenesis identify risk variant -specific epigenetic and transcriptional mechanisms. Knocking down two of the 17 genes, PPP2R5A and SH3PXD2B, shows a marked decrease in adipocyte lipidation and significantly alters adipocyte function and adipogenesis regulator genes, including DGAT2, LPL, ADIPOQ, PPARG, and SREBF1. Furthermore, the 17 genes capture a characteristic MASLD expression signature in subcutaneous adipose tissue.
CONCLUSIONS: Overall, we discover a significant cell-type level effect of abdominal obesity on MASLD and trace its biological effect to adipogenesis.
BACKGROUND: NIH grants R01HG010505, R01DK132775, and R01HL170604; the European Research Council (ERC) under the European Union\'s Horizon 2020 research and innovation program (Grant No. 802825), Academy of Finland (Grants Nos. 333021), the Finnish Foundation for Cardiovascular Research the Sigrid Jusélius Foundation and the Jane and Aatos Erkko Foundation; American Association for the Study of Liver Diseases (AASLD) Advanced Transplant Hepatology award and NIH/NIDDK (P30DK41301) Pilot and Feasibility award; NIH/NIEHS F32 award (F32ES034668); Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005-2021), the Academy of Finland grant (Contract no. 138006); Academy of Finland (Grant Nos 335443, 314383, 272376 and 266286), Sigrid Jusélius Foundation, Finnish Medical Foundation, Finnish Diabetes Research Foundation, Novo Nordisk Foundation (#NNF20OC0060547, NNF17OC0027232, NNF10OC1013354) and Government Research Funds to Helsinki University Hospital; Orion Research Foundation, Maud Kuistila Foundation, Finish Medical Foundation, and University of Helsinki.
METHODS: To elucidate the directional cell-type level biological mechanisms underlying the association between abdominal obesity and MASLD, we integrated adipose and liver single nucleus RNA-sequencing and bulk cis-expression quantitative trait locus (eQTL) data with the UK Biobank genome-wide association study (GWAS) data using colocalization. Then we used colocalized cis-eQTL variants as instrumental variables in Mendelian randomization (MR) analyses, followed by functional validation experiments on the target genes of the cis-eQTL variants.
RESULTS: We identified 17 colocalized abdominal obesity GWAS variants, regulating 17 adipose cell-type marker genes. Incorporating these 17 variants into MR discovers a putative tissue-of-origin, cell-type-aware causal effect of abdominal obesity on MASLD consistently with multiple MR methods without significant evidence for pleiotropy or heterogeneity. Single cell data confirm the adipocyte-enriched mean expression of the 17 genes. Our cellular experiments across human adipogenesis identify risk variant -specific epigenetic and transcriptional mechanisms. Knocking down two of the 17 genes, PPP2R5A and SH3PXD2B, shows a marked decrease in adipocyte lipidation and significantly alters adipocyte function and adipogenesis regulator genes, including DGAT2, LPL, ADIPOQ, PPARG, and SREBF1. Furthermore, the 17 genes capture a characteristic MASLD expression signature in subcutaneous adipose tissue.
CONCLUSIONS: Overall, we discover a significant cell-type level effect of abdominal obesity on MASLD and trace its biological effect to adipogenesis.
BACKGROUND: NIH grants R01HG010505, R01DK132775, and R01HL170604; the European Research Council (ERC) under the European Union\'s Horizon 2020 research and innovation program (Grant No. 802825), Academy of Finland (Grants Nos. 333021), the Finnish Foundation for Cardiovascular Research the Sigrid Jusélius Foundation and the Jane and Aatos Erkko Foundation; American Association for the Study of Liver Diseases (AASLD) Advanced Transplant Hepatology award and NIH/NIDDK (P30DK41301) Pilot and Feasibility award; NIH/NIEHS F32 award (F32ES034668); Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005-2021), the Academy of Finland grant (Contract no. 138006); Academy of Finland (Grant Nos 335443, 314383, 272376 and 266286), Sigrid Jusélius Foundation, Finnish Medical Foundation, Finnish Diabetes Research Foundation, Novo Nordisk Foundation (#NNF20OC0060547, NNF17OC0027232, NNF10OC1013354) and Government Research Funds to Helsinki University Hospital; Orion Research Foundation, Maud Kuistila Foundation, Finish Medical Foundation, and University of Helsinki.
摘要：
背景：腹型肥胖会增加非酒精性脂肪性肝病（NAFLD）的风险，现在被称为代谢功能障碍相关的脂肪变性肝病（MASLD）。
方法：为了阐明腹部肥胖与MASLD之间关联的定向细胞类型水平生物学机制，我们使用共定位法整合了脂肪和肝脏单核RNA测序和大量顺式表达定量性状基因座(eQTL)数据与UKBiobank全基因组关联研究(GWAS)数据.然后，我们在孟德尔随机化（MR）分析中使用共定位的顺式-eQTL变体作为工具变量，随后对顺式-eQTL变体的靶基因进行功能验证实验。
结果：我们确定了17个同位腹型肥胖GWAS变异，调节17个脂肪细胞型标记基因。将这17种变体整合到MR中发现了推定的起源组织，腹型肥胖对MASLD的细胞类型感知因果效应与多种MR方法一致,没有明显的多效性或异质性证据.单细胞数据证实了17个基因的富含脂肪细胞的平均表达。我们在人类脂肪形成的细胞实验确定了风险变异特异性表观遗传和转录机制。摧毁了17个基因中的两个，PPP2R5A和SH3PXD2B,显示脂肪细胞脂化显著减少，并显著改变脂肪细胞功能和脂肪生成调节基因，包括DGAT2，LPL，ADIPOQ,PPARG,和SREBF1。此外，这17个基因在皮下脂肪组织中捕获了特征性的MASLD表达特征。
结论：总体而言，我们发现腹型肥胖对MASLD有显著的细胞类型水平影响，并将其生物学效应追溯到脂肪生成。
背景：NIH授予R01HG010505，R01DK132775和R01HL170604；欧盟地平线2020研究与创新计划下的欧洲研究理事会（ERC）（批准号802825),芬兰学院（赠款编号333021)，芬兰心血管研究基金会，SigridJusélius基金会和JaneandAatosErkko基金会；美国肝病研究协会（AASLD）高级移植肝病奖和NIH/NIDDK（P30DK41301）试点和可行性奖；NIH/NIEHSF32奖（F32ES034668）；芬兰糖尿病研究基金会，库奥皮奥大学医院项目赠款(EVO/VTR赠款2005-2021)，芬兰科学院赠款(合同编号138006）；芬兰科学院（批准号335443、314383、272376和266286），SigridJusélius基金会,芬兰医学基金会,芬兰糖尿病研究基金会，诺和诺德基金会（#NNF20OC0060547，NNF17OC0027232，NNF10OC1013354）和赫尔辛基大学医院的政府研究基金；猎户座研究基金会，MaudKuistila基金会,完成医疗基金会，和赫尔辛基大学。
方法：为了阐明腹部肥胖与MASLD之间关联的定向细胞类型水平生物学机制，我们使用共定位法整合了脂肪和肝脏单核RNA测序和大量顺式表达定量性状基因座(eQTL)数据与UKBiobank全基因组关联研究(GWAS)数据.然后，我们在孟德尔随机化（MR）分析中使用共定位的顺式-eQTL变体作为工具变量，随后对顺式-eQTL变体的靶基因进行功能验证实验。
结果：我们确定了17个同位腹型肥胖GWAS变异，调节17个脂肪细胞型标记基因。将这17种变体整合到MR中发现了推定的起源组织，腹型肥胖对MASLD的细胞类型感知因果效应与多种MR方法一致,没有明显的多效性或异质性证据.单细胞数据证实了17个基因的富含脂肪细胞的平均表达。我们在人类脂肪形成的细胞实验确定了风险变异特异性表观遗传和转录机制。摧毁了17个基因中的两个，PPP2R5A和SH3PXD2B,显示脂肪细胞脂化显著减少，并显著改变脂肪细胞功能和脂肪生成调节基因，包括DGAT2，LPL，ADIPOQ,PPARG,和SREBF1。此外，这17个基因在皮下脂肪组织中捕获了特征性的MASLD表达特征。
结论：总体而言，我们发现腹型肥胖对MASLD有显著的细胞类型水平影响，并将其生物学效应追溯到脂肪生成。
背景：NIH授予R01HG010505，R01DK132775和R01HL170604；欧盟地平线2020研究与创新计划下的欧洲研究理事会（ERC）（批准号802825),芬兰学院（赠款编号333021)，芬兰心血管研究基金会，SigridJusélius基金会和JaneandAatosErkko基金会；美国肝病研究协会（AASLD）高级移植肝病奖和NIH/NIDDK（P30DK41301）试点和可行性奖；NIH/NIEHSF32奖（F32ES034668）；芬兰糖尿病研究基金会，库奥皮奥大学医院项目赠款(EVO/VTR赠款2005-2021)，芬兰科学院赠款(合同编号138006）；芬兰科学院（批准号335443、314383、272376和266286），SigridJusélius基金会,芬兰医学基金会,芬兰糖尿病研究基金会，诺和诺德基金会（#NNF20OC0060547，NNF17OC0027232，NNF10OC1013354）和赫尔辛基大学医院的政府研究基金；猎户座研究基金会，MaudKuistila基金会,完成医疗基金会，和赫尔辛基大学。
