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LncPRYP4-3 serves as a novel diagnostic biomarker for dissecting subtypes of metabolic associated fatty liver disease by targeting RPS4Y2

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Abstract

Longitudinal studies have improved current diagnostics and management of metabolic associated fatty liver disease (MAFLD) patients by liver biopsy and therapeutic intervention, yet the deficiency of biomarker spectrum for dissecting subtypes largely hinders the symptomatic treatment. We originally enriched serum from peripheral blood of 618 healthy donors (HD) and 580 MAFLD (400 NAFL, 180 NASH) patients according to multiple clinicopathological indicators. Microarray profiling and qRT-PCR were conducted to identify lncRNAs as candidate biomarkers of MAFLD. Then, we analyzed the matching score of the indicated lncRNA with CAP or MAFLD-associated pathological parameters as well. Additionally, we took advantage of interaction network together with gene expression profiling analysis to further explore the underlying target genes of the identified lncRNA. Herein, we found CAP in nearly all of the NAFL (399/400) and NASH (179/180) patients was higher than that in the HDs (611/618). The differentially expressed lncRNAs were involved in multiple metabolic or immunologic processes by regulating MAFLD-associated pathways. Of them, serum lncPRYP4-3 was identified as a novel candidate biomarker of MAFLD, which was further confirmed by correlation analysis with clinical indicators. Thereafter, we deduced PRS4Y2 was a candidate target of lncPRYP4-3 and mediated the dysfunction in NAFL and NASH patients. Serum lncPRYP4-3 served as a novel biomarker of MAFLD and helped distinguish the subtypes and benefit precise intervention therapy. Our findings also provided overwhelming new evidence for the alteration in biological processes and gene ontology in MAFLD patients.

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Abbreviations

CAP:

Controlled attenuation parameter

LSM:

Liver stiffness measurement

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

BMI:

Body mass index

BUN:

Blood urea nitrogen

GGT:

γ-Glutamyl transferase

ALP:

Alkaline phosphatase

TB:

Total bilirubin

LDL-C:

Low-density lipoprotein-cholesterol

HDL-C:

High-density lipoprotein-cholesterol

TG:

Triglyceride

TC:

Total cholesterol

SUA:

Serum uric acid

PChE:

Pseudocholinesterase

PLT:

Platelet count

FBG:

Fasting blood glucose

NAFL:

Nonalcoholic fatty liver

NASH:

Nonalcoholic steatohepatitis

MAFLD:

Metabolic associated fatty liver disease.

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Acknowledgements

The work was supported by the National Natural Science Foundation of China (81660410), Natural Science Foundation of Tianjin (19JCQNJC12500), Science and Technology Project of Tianjin (17ZXSCSY00030), Project funded by China Postdoctoral Science Foundation (2019M661033), Natural Science Foundation of Yunnan (2017FE468-174) and Yunnan Science and Technology Project (2015HB073, CXTD201610, L-2017018, 2018NS0100), Nanyang Science and Technology Project of He-nan Province (JCQY012), Key project funded by Department of Science and Technology of Shangrao City (2020, to ZCH), the Reserve Training Project of "Thousand" Project of Health Science and Technology Talents in Kunming (2019-sw-52), NHC Key Laboratory of Drug Addiction Medicine (Kunming Medical University). The authors thank all the nurses and patients involved in this study. We also thank the precision medicine division of Health-Biotech (Tianjin) Stem Cell Research Institute Co., Ltd. and the enterprise postdoctoral working station of Tianjin Chase Sun Pharmaceutical Co., Ltd. for their technical support.

Funding

The work was supported by the National Natural Science Foundation of China (81660410), Natural Science Foundation of Tianjin (19JCQNJC12500), Science and Technology Project of Tianjin (17ZXSCSY00030), Project funded by China Postdoctoral Science Foundation (2019M661033), Natural Science Foundation of Yunnan (2017FE468-174) and Yunnan Science and Technology Project (2015HB073, CXTD201610, L-2017018, 2018NS0100), Nanyang Science and Technology Project of He-nan Province (JCQY012), Key project funded by Department of Science and Technology of Shangrao City (2020, to ZCH), the Reserve Training Project of "Thousand" Project of Health Science and Technology Talents in Kunming (2019-sw-52), NHC Key Laboratory of Drug Addiction Medicine (Kunming Medical University).

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Author notes

  1. Hongju Yang, Qian Li, Leisheng Zhang those authors contributed equally to this work

Authors and Affiliations

  1. Division of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Kunming, 650031, People’s Republic of China

    Hongju Yang, Mei Zhu, Fenglin Xue, Qiu Qu, Yaling Lao, Zheng Ding, Changyan Xiao & Kunhua Wang

  2. Transfusion Medicine Research Department, Yunnan Kunming Blood Center, Kunming, 650011, People’s Republic of China

    Qian Li

  3. The Postdoctoral Research Station, School of Medicine, Nankai University, Tianjin, 300071, People’s Republic of China

    Leisheng Zhang

  4. State Key Laboratory of Experimental Hematology and National Clinical Research Center for Blood Disease, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, People’s Republic of China

    Leisheng Zhang

  5. Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming, 650031, People’s Republic of China

    Jie Niu

  6. Division of Gastroenterology, The Second Affiliated Hospital of Kunming Medical University, Kunming, 650101, China

    Lihong Yang

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  1. Hongju Yang
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Contributions

HY and QL contributed to collection and assembly of data, manuscript writing; LZ, MZ, JN, FX, LY, QQ, YL, ZD and CX contributed to collection and assembly of data; and HY, LZ and KW contributed to conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript.

Corresponding authors

Correspondence to Hongju Yang, Leisheng Zhang or Kunhua Wang.

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All data generated or analyzed during this study are included in this published article and its supplementary information files. Meanwhile, the datasets used and analyzed during the current study are also available from the corresponding author on reasonable request.

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The study was performed in accordance with the principles set by the Declaration of Helsinki, and was approved by the ethics committee of First Affiliated Hospital of Kunming Medical University (approval number: 2020-L-08). Informed consent was obtained from all individual participants included in the study.

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Yang, H., Li, Q., Zhang, L. et al. LncPRYP4-3 serves as a novel diagnostic biomarker for dissecting subtypes of metabolic associated fatty liver disease by targeting RPS4Y2. Clin Exp Med 20, 587–600 (2020). https://doi.org/10.1007/s10238-020-00636-1

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