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Updated: Jul 15, 2025

Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-radioactive L-azidohomoalanine Labeling Method
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The causal effect of mTORC1-dependent circulating protein levels on nonalcoholic fatty liver disease: A Mendelian

Xiangyu Yan1, Songhan Huang1, Hongxin Li1

  • 1Department of Hepatobiliary Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250021, China.

Digestive and Liver Disease : Official Journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver
|October 1, 2023
PubMed
Abstract

Insights

Elevated levels of mechanistic target of rapamycin (mTOR)-dependent Eukaryotic Initiation Factor 4E (eIF4E) may causally increase the risk of nonalcoholic fatty liver disease (NAFLD). This Mendelian randomization study identified eIF4E as a potential causal factor in NAFLD development.

Area of Science:

  • Genetics
  • Metabolic Diseases
  • Molecular Biology

Background:

  • The mechanistic target of rapamycin (mTOR) pathway is implicated in nonalcoholic fatty liver disease (NAFLD) pathogenesis.
  • The specific causal roles of mTOR downstream proteins in NAFLD remain largely uncharacterized.

Purpose of the Study:

  • To investigate the causal effect of key mTOR-dependent proteins, including Eukaryotic Initiation Factor 4E (eIF4E), on NAFLD risk using Mendelian randomization.
  • To assess the association between circulating levels of eIF4EBPs, RP-S6K, eIF4E, eIF4A, and eIF4G and the incidence of NAFLD.

Main Methods:

  • A two-sample Mendelian randomization (MR) study design was employed.
  • Inverse-variance weighted (IVW) method was used for causal effect estimation in discovery and validation datasets.
  • Genome-Wide Association Study (GWAS) derived single-nucleotide polymorphisms (SNPs) were utilized to predict protein levels.

Main Results:

  • Mendelian randomization analysis revealed a significant causal effect of Eukaryotic Initiation Factor 4E (eIF4E) on NAFLD risk.
  • This association was consistently observed in both the discovery (OR = 1.339, P = 0.037) and validation (OR = 1.0007, P = 0.022) stages.
  • Sensitivity analyses confirmed the robustness of the findings.

Conclusions:

  • Elevated plasma levels of mechanistic target of rapamycin (mTOR)-dependent Eukaryotic Initiation Factor 4E (eIF4E) are suggested to have a causal role in the development of nonalcoholic fatty liver disease (NAFLD).
  • These findings highlight eIF4E as a potential therapeutic target for NAFLD.
Keywords:
Causal associationMendelian randomizationNonalcoholic fatty liver diseasemTORC1

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