Shepherd EL, Karim S, Newsome PN, Lalor PF. Inhibition of vascular adhesion protein-1 modifies hepatic steatosis in vitro and in vivo. World J Hepatol 2020; 12(11): 931-948 [PMID: 33312420 DOI: 10.4254/wjh.v12.i11.931]
Corresponding Author of This Article
Patricia F Lalor, BSc, PhD, Academic Research, Reader (Associate Professor), Centre for Liver and Gastroenterology Research, Birmingham National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham B15 2TT, West Midlands, United Kingdom. p.f.lalor@bham.ac.uk
Research Domain of This Article
Gastroenterology & Hepatology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
World J Hepatol. Nov 27, 2020; 12(11): 931-948 Published online Nov 27, 2020. doi: 10.4254/wjh.v12.i11.931
Inhibition of vascular adhesion protein-1 modifies hepatic steatosis in vitro and in vivo
Emma L Shepherd, Sumera Karim, Philip N Newsome, Patricia F Lalor
Emma L Shepherd, Sumera Karim, Philip N Newsome, Patricia F Lalor, Centre for Liver and Gastroenterology Research, Birmingham National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, West Midlands, United Kingdom
Philip N Newsome, Liver Unit, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2TT, West Midlands, United Kingdom
Author contributions: Shepherd EL, Karim S, Newsome PN and Lalor PF contributed to the writing and revising of the manuscript.
Institutional review board statement: The study was reviewed and approved by The Black Country Research Ethics Committee (06/Q702/61).
Institutional animal care and use committee statement: All mice were maintained and housed under conventional conditions in the Biomedical Services Unit at the University of Birmingham, United Kingdom. All animal experiments were performed under a Home Office project license in accordance with United Kingdom legislation and welfare guidelines, and studies were approved by the local ethical review board.
Conflict-of-interest statement: This study includes independent research supported by the Birmingham National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre based at the University of Birmingham. The views expressed are those of the authors and not necessarily those of the NHS, the National Institute of Health Research or the Department of Health and Social Science. These studies were in part funded by a Biotechnology and Biosciences Research Council case studentship (BB/G529824/1) to P. F. Lalor for S. Karim. No other conflict of interest.
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.
Corresponding author: Patricia F Lalor, BSc, PhD, Academic Research, Reader (Associate Professor), Centre for Liver and Gastroenterology Research, Birmingham National Institute for Health Research, Birmingham Biomedical Research Centre, Institute of Immunology and Immunotherapy, University of Birmingham, Edgbaston, Birmingham B15 2TT, West Midlands, United Kingdom. p.f.lalor@bham.ac.uk
Received: June 15, 2020 Peer-review started: June 15, 2020 First decision: June 20, 2020 Revised: July 23, 2020 Accepted: September 15, 2020 Article in press: September 15, 2020 Published online: November 27, 2020 Processing time: 161 Days and 18.5 Hours
ARTICLE HIGHLIGHTS
Research background
Current standard of care for non-alcoholic fatty liver disease (NAFLD) patients varies according to disease stage, but includes lifestyle interventions common insulin sensitizers, antioxidants and lipid modifiers. However, to date specific therapies for have shown little histological or fibrosis stage improvement in large clinical trials and there is still no licensed therapy for NAFLD. Given the high prevalence, limited treatment options and significant screening costs for the general population, new treatments are urgently required.
Research motivation
Vascular adhesion protein-1 (VAP-1) is an enzyme with proven contributions to systemic and hepatic glucose handling, inflammation and fibrosis. We now show an additional role in hepatic steatosis.
Research objectives
In the current investigation, we aimed to assess the potential for inhibition of the amine oxidase enzyme VAP-1 to modify hepatic lipid accumulation in NAFLD.
Research methods
We have used a combination of human cell cultures, a murine model and human precision cut liver slices to understand the contribution of the semicarbazide sensitive amine oxidase enzyme VAP-1 to lipid handling in NAFLD. This molecule is of increasing therapeutic interest due to its ability to regulate hepatic inflammation and fibrosis.
Research results
VAP-1 increases lipid accumulation and reduces triglyceride export by hepatocytes. This is linked to alterations in expression of key lipid transporters including FABP1, 2 and 4, FATP2-5 and LRP1 and key regulators such as PPARα. In agreement, VAP-1 deficient mice are protected against steatosis on high fat diet.
Research conclusions
We suggest the multifaceted effects of VAP-1 within the liver in NAFLD make it an interesting target for pharmacological intervention.
Research perspectives
We would argue that the increased pharmaceutical interest in amine oxidase inhibitors is well placed.
