Elevation of plasma tRNA fragments as a promising biomarker for liver fibrosis in nonalcoholic fatty liver disease

Peng Huang,Kuang-Ye Zhu,Tian-Yi Zhang,Feng Dai,Zhen-Zhou Li,Fei-Zhou Huang,Biao Tu,Chuan-Zheng Sun,Huai-Zheng Liu,Hui-Jun Liao

doi:10.1038/s41598-021-85421-0

Abstract

Fibrotic tissue remodelling in nonalcoholic fatty liver disease (NAFLD) will probably emerge as the leading cause of end-stage liver disease in the coming decades, but the ability to diagnose liver fibrosis in NAFLD patients noninvasively is limited. The abnormal expression of tRNA-derived small RNA (tsRNA) in plasma provides a novel idea for noninvasive diagnosis of various diseases, however, the relationship between tsRNAs and NAFLD is still unknown. Here, we took advantage of small RNA-Seq technology to profile tsRNAs in NAFLD patients and found the ubiquitous presence of hepatic tsRNAs secreted into circulating blood. Verification in a cohort of 114 patients with NAFLD and 42 patients without NAFLD revealed that three tsRNAs (tRF-Val-CAC-005, tiRNA-His-GTG-001, and tRF-Ala-CGC-006) were significantly elevated in the plasma of NAFLD patients, and the expression level are associated with NAFLD activity score (calculated from 0 to 8) and fibrosis stage (scored from 0 to 4). In mouse models, we further found that increased plasma levels of these three tsRNAs were positively correlated with the degree of liver fibrosis. Our study potentially identifies a new class of NAFLD biomarkers and reveal the possible existence of tsRNAs in the blood that can be used to predict fibrogenesis risk in patients diagnosed with NAFLD.

Highlights

Abbreviations NAFLD Nonalcoholic fatty liver disease nonalcoholic steatohepatitis (NASH) Nonalcoholic steatohepatitis NAFLD Fibrosis Score (NFS) Fibrosis score Aspartate Transaminase (AST) Aspartate transaminase AST to Platelet Ratio Index (APRI) Platelet ratio index Fibrosis-4 Score (FIB-4) The fibrosis-4 score Small noncoding RNAs (sncRNAs) Novel small non-coding RNAs tRNA-derived small RNA (tsRNA) TRNA-derived small RNAs nt Nucleotides HC High-cholesterol bile duct ligation (BDL) Bile duct ligation ROC Receiver operating characteristic area under the curve (AUC) Area under the curve ALT Alanine aminotransferase gamma-glutamyl transferase (GGT) Gamma-glutamyl transferase alkaline phosphatase (ALP) Alkaline phosphatase total bilirubin (Tbil) Total bilirubin direct bilirubin (Dbil) Direct bilirubin fasting blood glucose (FBG) Fasting blood glucose
NAFLD refers to a spectrum ranging from noninflammatory isolated steatosis to nonalcoholic steatohepatitis (NASH), which is characterized by steatosis, necroinflammatory changes, and varying degrees of liver fibrosis[2]
Body mass index (BMI), low-density lipoprotein (LDL), triglyceride (TG), total cholesterol (TC), and NAFLD activity score were significantly higher in the NAFLD group than in the control group

Summary

Introduction

Abbreviations NAFLD Nonalcoholic fatty liver disease NASH Nonalcoholic steatohepatitis NFS Fibrosis score AST Aspartate transaminase APRI Platelet ratio index FIB-4 The fibrosis-4 score sncRNAs Novel small non-coding RNAs tsRNAs TRNA-derived small RNAs nt Nucleotides HC High-cholesterol BDL Bile duct ligation ROC Receiver operating characteristic AUC Area under the curve ALT Alanine aminotransferase GGT Gamma-glutamyl transferase ALP Alkaline phosphatase Tbil Total bilirubin Dbil Direct bilirubin FBG Fasting blood glucose. The most common scores that combine several clinical parameters are the NAFLD Fibrosis Score (NFS), the Aspartate Transaminase (AST) to Platelet Ratio Index (APRI), and the Fibrosis-4 Score (FIB-4)[5]. Small noncoding RNAs (sncRNAs) have recently emerged as potential biomarkers since changes in miRNA expression profiles, such as miR-122, miR-34a, and miR-192, have been observed at various stages of NAFLD in both human patients and animal models[6]

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Conclusion