Evidence map›Paper›PMID 37224770›Full record

ArticleEBioMedicine2023

Cross-tissue omics analysis discovers ten adipose genes encoding secreted proteins in obesity-related non-alcoholic fatty liver disease.

Nicholas Darci-Maher, Marcus Alvarez, Uma Thanigai Arasu, Ilakya Selvarajan, Seung Hyuk T Lee, David Z Pan, Zong Miao, Sankha Subhra Das, Dorota Kaminska, Tiit Örd and 10 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in EBioMedicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
22citing papers in PubMed, 1 pooled it
14.8field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

22 citing papers in PubMed, 1 synthesis or guideline pooled it, 65 citations in OpenAlex.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

20 authors at 5 institutions in 3 countries.

Nicholas Darci-MaherDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA.
Marcus AlvarezDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA.
Uma Thanigai ArasuA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Ilakya SelvarajanA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Seung Hyuk T LeeDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA.
David Z PanDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA.
Zong MiaoDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA.
Sankha Subhra DasDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA.
Dorota KaminskaDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA; Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, USA.
Tiit ÖrdA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Jihane N BenhammouVatche and Tamar Manoukian Division of Digestive Diseases, and Gastroenterology, Hepatology and Parenteral Nutrition, David Geffen School of Medicine at UCLA and VA Greater Los Angeles HCS, Los Angeles, USA.
Martin WabitschDivision of Pediatric Endocrinology and Diabetes, Department of Pediatrics and Adolescent Medicine, University of Ulm, Ulm, Germany.
Joseph R PisegnaDepartment of Medicine and Human Genetics, Division of Gastroenterology, Hepatology and Parenteral Nutrition, David Geffen School of Medicine at UCLA and VA Greater Los Angeles HCS, Los Angeles, USA.
Ville MännistöDepartment of Medicine, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
Kirsi H PietiläinenObesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Obesity Center, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.
Markku LaaksoInstitute of Clinical Medicine, Kuopio University Hospital, University of Eastern Finland, Kuopio, Finland.
Janet S SinsheimerDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA; Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, USA; Department of Computational Medicine, David Geffen School of Medicine at UCLA, Los Angeles, USA.
Minna U KaikkonenA. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Jussi PihlajamäkiInstitute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland; Department of Medicine, Endocrinology and Clinical Nutrition, Kuopio University Hospital, Kuopio, Finland.
Päivi PajukantaDepartment of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, USA; Bioinformatics Interdepartmental Program, UCLA, Los Angeles, USA; Institute for Precision Health, David Geffen School of Medicine at UCLA, Los Angeles, USA. Electronic address: ppajukanta@mednet.ucla.edu.
University of California, Los Angeles · USUniversity of Eastern Finland · FIVA Greater Los Angeles Healthcare System · USUniversität Ulm · DEUniversity of Helsinki · FI

Funding

Methods for Genomic Analysis in Heterogeneous TissuesR01HG010505 · NHGRI · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI HALPERIN, ERAN · 2019 to 2022
$2.6M
Genetics of adipose cell-type expression and cardiometabolic traitsR01DK132775 · NIDDK · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI MOHLKE, KAREN L., PAJUKANTA, PAIVI · 2022 to 2025
$2.4M
NHGRI NIH HHS R01 HG010505NIDDK NIH HHS R01 DK132775
6 · The paper itself

Abstract

backgroundNon-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.

methodsTo 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.

findingsWe 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.

interpretationOur 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.

fundingThe work was supported by NIH grants R01HG010505 and R01DK132775. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The KOBS study (J. P.) was supported by the Finnish Diabetes Research Foundation, Kuopio University Hospital Project grant (EVO/VTR grants 2005-2019), and the Academy of Finland grant (Contract no. 138006). This study was funded by the European Research Council under the European Union's Horizon 2020 research and innovation program (Grant No. 802825 to M. U. K.). K. H. P. was funded by the Academy of Finland (grant numbers 272376, 266286, 314383, and 335443), the Finnish Medical Foundation, Gyllenberg Foundation, Novo Nordisk Foundation (grant numbers NNF10OC1013354, NNF17OC0027232, and NNF20OC0060547), Finnish Diabetes Research Foundation, Finnish Foundation for Cardiovascular Research, University of Helsinki, and Helsinki University Hospital and Government Research Funds. I. S. was funded by the Instrumentarium Science Foundation. Personal grants to U. T. A. were received from the Matti and Vappu Maukonen Foundation, Ella och Georg Ehrnrooths Stiftelse and the Finnish Foundation for Cardiovascular Research.

Indexed as

Non-alcoholic Fatty Liver DiseaseBiomarkersGenome-Wide Association StudyHumansLiverObesityBiomarkersAdipogenesiscis regulatory variantsDual-tissue transcriptomics screeningLiver histologyNon-alcoholic fatty liver diseaseObesitySerum biomarkers

Identifiers

PMID37224770
PMCPMC10277924
OpenAlexW4377263717

What Socratic holds

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LicenceCC BY
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.