Basic Study
Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 28, 2023; 29(28): 4433-4450
Published online Jul 28, 2023. doi: 10.3748/wjg.v29.i28.4433
F-box only protein 2 exacerbates non-alcoholic fatty liver disease by targeting the hydroxyl CoA dehydrogenase alpha subunit
Zhi Liu, Ning-Yuan Chen, Zhao Zhang, Sai Zhou, San-Yuan Hu
Zhi Liu, San-Yuan Hu, Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, Shandong Province, China
Ning-Yuan Chen, Zhao Zhang, Department of General Surgery, Shandong Provincial Qian Foshan Hospital, Shandong University, Jinan 250014, Shandong Province, China
Sai Zhou, Department of General Surgery, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan 250117, Shandong Province, China
Author contributions: Hu SY and Liu Z contributed equally to this work; Hu SY and Liu Z designed the research study; Liu Z, Chen NY, Zhang Z, and Zhou S performed the research; Liu Z and Chen NY contributed new reagents and analytic tools; Liu Z and Chen NY analyzed the data and wrote the manuscript; and all authors have read and approve the final manuscript.
Supported by the National Natural Science Foundation of China, No. 82070869 and 82270914.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of Qilu Hospital of Shandong University.
Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals (license No. S453, Institutional Animal Care and Use Committee of Shandong Provincial Qian Foshan Hospital).
Informed consent statement: Written informed consent was obtained from the patients and their families.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: San-Yuan Hu, Doctor, MD, Chief Doctor, Chief Physician, Doctor, Full Professor, Professor, Surgeon, Department of General Surgery, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, Jinan 250012, Shandong Province, China. husanyuan1962@hotmail.com
Received: May 24, 2023
Peer-review started: May 24, 2023
First decision: June 14, 2023
Revised: June 19, 2023
Accepted: July 11, 2023
Article in press: July 11, 2023
Published online: July 28, 2023
Processing time: 63 Days and 10.5 Hours
Abstract
BACKGROUND

Non-alcoholic fatty liver disease (NAFLD) is a major health burden with an increasing global incidence. Unfortunately, the unavailability of knowledge underlying NAFLD pathogenesis inhibits effective preventive and therapeutic measures.

AIM

To explore the molecular mechanism of NAFLD.

METHODS

Whole genome sequencing (WGS) analysis was performed on liver tissues from patients with NAFLD (n = 6) and patients with normal metabolic conditions (n = 6) to identify the target genes. A NAFLD C57BL6/J mouse model induced by 16 wk of high-fat diet feeding and a hepatocyte-specific F-box only protein 2 (FBXO2) overexpression mouse model were used for in vivo studies. Plasmid transfection, co-immunoprecipitation-based mass spectrometry assays, and ubiquitination in HepG2 cells and HEK293T cells were used for in vitro studies.

RESULTS

A total of 30982 genes were detected in WGS analysis, with 649 up-regulated and 178 down-regulated. Expression of FBXO2, an E3 ligase, was upregulated in the liver tissues of patients with NAFLD. Hepatocyte-specific FBXO2 overexpression facilitated NAFLD-associated phenotypes in mice. Overexpression of FBXO2 aggravated odium oleate (OA)-induced lipid accumulation in HepG2 cells, resulting in an abnormal expression of genes related to lipid metabolism, such as fatty acid synthase, peroxisome proliferator-activated receptor alpha, and so on. In contrast, knocking down FBXO2 in HepG2 cells significantly alleviated the OA-induced lipid accumulation and aberrant expression of lipid metabolism genes. The hydroxyl CoA dehydrogenase alpha subunit (HADHA), a protein involved in oxidative stress, was a target of FBXO2-mediated ubiquitination. FBXO2 directly bound to HADHA and facilitated its proteasomal degradation in HepG2 and HEK293T cells. Supplementation with HADHA alleviated lipid accumulation caused by FBXO2 overexpression in HepG2 cells.

CONCLUSION

FBXO2 exacerbates lipid accumulation by targeting HADHA and is a potential therapeutic target for NAFLD.

Keywords: F-box only protein 2; Nonalcoholic fatty liver disease; The hydroxyl CoA dehydrogenase alpha subunit; Liver steatosis; Ubiquitination; Lipid accumulation

Core Tip: This study involves an assessment of the role of F-box only protein 2 (FBXO2) in non-alcoholic fatty liver disease (NAFLD). First, based on the whole genome sequencing analysis results of liver tissues from normal controls and patients with NAFLD, the expression of FBXO2 was found to be increased during NAFLD. Hepatocyte-specific FBXO2 overexpression facilitated NAFLD-associated phenotypes in mice. In contrast, the knockdown of FBXO2 expression of HepG2 cells significantly alleviated oleate-induced lipid accumulation. Mechanistically, the hydroxyl CoA dehydrogenase alpha subunit, a protein with known role in oxidative stress reaction, is one of the protein substrates of FBXO2-mediated ubiquitination.