Basic Study
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Nov 27, 2024; 16(11): 1290-1305
Published online Nov 27, 2024. doi: 10.4254/wjh.v16.i11.1290
Non-invasively differentiate non-alcoholic steatohepatitis by visualizing hepatic integrin αvβ3 expression with a targeted molecular imaging modality
Xiao-Quan Huang, Ling Wu, Chun-Yan Xue, Chen-Yi Rao, Qing-Qing Fang, Ying Chen, Cao Xie, Sheng-Xiang Rao, Shi-Yao Chen, Feng Li
Xiao-Quan Huang, Ling Wu, Chun-Yan Xue, Chen-Yi Rao, Shi-Yao Chen, Feng Li, Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Qing-Qing Fang, Ying Chen, Shi-Yao Chen, Feng Li, Department of Gastroenterology, Minhang Hospital, Fudan University, Shanghai 201100, China
Cao Xie, Department of Pharmacy, Fudan University, Shanghai 200032, China
Sheng-Xiang Rao, Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Co-first authors: Xiao-Quan Huang and Ling Wu.
Author contributions: Li F and Huang XQ designed the research study; Huang XQ, Wu L, Xue CY, Rao CY, Fang QQ and Chen Y performed the research; Huang XQ, Wu L, Xue CY and Rao CY collected and analyzed data; Xie C and Rao SX conducted animal imaging and analysis; Wu L and Huang XQ wrote the manuscript; Li F, Huang XQ, Wu L, Chen SY revised the manuscript; All authors have read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81670513; and Young Scientists Fund of the National Natural Science Foundation of China, No. 81900511.
Institutional review board statement: This study does not involve human subject research.
Institutional animal care and use committee statement: This study was performed in line with the Declaration of Helsinki and the ethical approval was obtained from the Institutional Ethical Committee of Animal Experimentation, Zhongshan Hospital affiliated to Fudan University.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
Data sharing statement: Data will be made available upon reasonable request.
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: Feng Li, MD, Chief Physician, Research Scientist, Senior Scientist, Staff Physician, Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai 200032, China. li.feng2@zs-hospital.sh.cn
Received: March 26, 2024
Revised: August 27, 2024
Accepted: October 20, 2024
Published online: November 27, 2024
Processing time: 224 Days and 14.9 Hours
Abstract
BACKGROUND

Non-invasive methods to diagnose non-alcoholic steatohepatitis (NASH), an inflammatory subtype of non-alcoholic fatty liver disease (NAFLD), are currently unavailable.

AIM

To develop an integrin αvβ3-targeted molecular imaging modality to differentiate NASH.

METHODS

Integrin αvβ3 expression was assessed in Human LO2 hepatocytes Scultured with palmitic and oleic acids (FFA). Hepatic integrin αvβ3 expression was analyzed in rabbits fed a high-fat diet (HFD) and in rats fed a high-fat, high-carbohydrate diet (HFCD). After synthesis, cyclic arginine-glycine-aspartic acid peptide (cRGD) was labeled with gadolinium (Gd) and used as a contrast agent in magnetic resonance imaging (MRI) performed on mice fed with HFCD.

RESULTS

Integrin αvβ3 was markedly expressed on FFA-cultured hepatocytes, unlike the control hepatocytes. Hepatic integrin αvβ3 expression significantly increased in both HFD-fed rabbits and HFCD-fed rats as simple fatty liver (FL) progressed to steatohepatitis. The distribution of integrin αvβ3 in the liver of NASH cases largely overlapped with albumin-positive staining areas. In comparison to mice with simple FL, the relative liver MRI-T1 signal value at 60 minutes post-injection of Gd-labeled cRGD was significantly increased in mice with steatohepatitis (P < 0.05), showing a positive correlation with the NAFLD activity score (r = 0.945; P < 0.01). Hepatic integrin αvβ3 expression was significantly upregulated during NASH development, with hepatocytes being the primary cells expressing integrin αvβ3.

CONCLUSION

After using Gd-labeled cRGD as a tracer, NASH was successfully distinguished by visualizing hepatic integrin αvβ3 expression with MRI.

Keywords: Non-alcoholic steatohepatitis; Cyclic peptides; Magnetic resonance imaging; Non-invasive diagnosis; Hepatic integrin αvβ3

Core Tip: Early identification of non-alcoholic steatohepatitis (NASH) patients and accurate assessment of non-alcoholic fatty liver disease severity are crucial for improving patient outcomes. Currently, no non-invasive method can replace liver biopsy to accurately discern NASH. Hepatic integrin αvβ3 expression significantly increased as simple fatty liver progressed to steatohepatitis. Inflammatory-injured hepatocytes, which might be the primary cells expressing integrin αvβ3 in steatohepatitis, were identified on the basis of steatosis. Utilizing gadolinium-labeled cyclic arginine-glycine-aspartic acid peptide as a contrast agent, steatohepatitis was successfully differentiated by visualizing hepatic integrin αvβ3 expression using a magnetic resonance imaging modality.