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Research Paper|Volume 14, Issue 7|pp 3259—3275

Cholesterol-induced leucine aminopeptidase 3 (LAP3) upregulation inhibits cell autophagy in pathogenesis of NAFLD

Lina Feng1,2, Yanping Chen3,4, Ke Xu5, Yingchao Li6, Farooq Riaz1,2, Kaikai Lu1,2, Qian Chen1,2, Xiaojuan Du1,2, Litao Wu1,2, Dan Cao4, Chunyan Li3, Shemin Lu1,2, Dongmin Li1,2
  • 1Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Xi’an Jiaotong University Health Science Center, Xi’an, Shaan Xi 710061, China
  • 2Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Ministry of Education of China, Xi’an, Shaan Xi 710061, China
  • 3Department of Infectious Diseases, The Affiliated Hospital of Yan’an University, Yan’an, China
  • 4Department of Infectious Diseases, Yan’an Second People’s Hospital, Yan’an, China
  • 5Department of Joint Surgery, Xi’an Hong Hui Hospital, Xi’an Jiaotong University Health Science Center, Xi’an, China
  • 6Department of Gastroenterology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, China
* Equal contribution
Received: January 19, 2022Accepted: March 28, 2022Published: April 11, 2022
https://doi.org/10.18632/aging.204011

Copyright: © 2022 Feng et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Objectives: Leucine aminopeptidase 3 (LAP3), an M1 member of leucine aminopeptidase, was reported to be significantly upregulated in serum of nonalcoholic fatty liver disease (NAFLD) patients. However, the underlying mechanisms of LAP3 in NAFLD pathogenesis are still unknown. We aim to investigate the role of LAP3 in NAFLD pathogenesis and explore whether LAP3 has the potential to be a candidate biomarker in serum for NAFLD diagnosis.

Methods: Liver tissues and serum from NASH rats, serum from patients with NAFLD were obtained to evaluate the LAP3 expression. Detection of GSSG/GSH, intracellular reactive oxygen species (ROS), and LC3 expression by elevation/ reduction of LAP3 expression to determine the role of LAP3 in NAFLD pathogenesis. Finally, the correlation analysis was conducted to evaluate the association between LAP3 expression and clinical indexes of NAFLD.

Results: LAP3 expression was upregulated in hepatocytes and serum in E3 rats with NASH after 6-month HFD feeding. Cholesterol (CHO) dramatically upregulated LAP3 in LO2 cells, and then lead to negative regulation of autophagy. Moreover, LAP3 levels were also significantly increased in NAFLD patients compared to healthy controls. Correlation analysis revealed that serum LAP3 levels were positively correlated with TG, γ-glutamyltranspeptidase (GGT), and fasting blood glucose levels, while there was a negative correlation with HDL levels.

Conclusions: The cholesterol-dependent upregulation of LAP3 in hepatocytes plays a critical role in the pathogenesis of NAFLD via inhibiting autophagy. Moreover, LAP3 could serve as a potential novel candidate biomarker for the diagnosis of NAFLD.