Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Dec 28, 2018; 24(48): 5477-5490
Published online Dec 28, 2018. doi: 10.3748/wjg.v24.i48.5477
Mismatched effects of receptor interacting protein kinase-3 on hepatic steatosis and inflammation in non-alcoholic fatty liver disease
Waqar Khalid Saeed, Dae Won Jun, Kiseok Jang, Sang Bong Ahn, Ju Hee Oh, Yeon Ji Chae, Jai Sun Lee, Hyeon Tae Kang
Waqar Khalid Saeed, Dae Won Jun, Department of Gastroenterology, Hanyang University College of Medicine, Seoul 04763, South Korea
Kiseok Jang, Department of Pathology, Hanyang University College of Medicine, Seoul 04763, South Korea
Sang Bong Ahn, Department of Internal Medicine, Eulji University, Daejeon 34824, South Korea
Ju Hee Oh, Yeon Ji Chae, Jai Sun Lee, Hyeon Tae Kang, Department of Translational Medicine, Hanyang University College of Medicine, Seoul 04763, South Korea
Author contributions: Saeed WK drafted the manuscript; Jun DW designed the research and supervised the project; Oh JH, Chae YJ, Lee JS, and Kang HT collected the data; Lee JS analyzed the data; Jang K analyzed the histology data; Ahn SB supervised and revised the manuscript.
Supported by National Research Foundation of Korea (NRF), funded by the South Korean Government, No. NRF-2017M3A9C8028794.
Institutional animal care and use committee statement: All the experimental procedures were approved by the Hanyang University Institutional Animal Care and Use Committee of (HY-IACUC-16-0075).
Conflict-of-interest statement: The authors have declared no conflicts of interest.
Data sharing statement: No additional data is available.
Open-Access: 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:
Corresponding author: Dae Won Jun, MD, PhD, Professor, Department of Internal Medicine, Hanyang University College of Medicine, 222-1 Wangsimni-ro, Seongdong-gu, Seoul 04763, South Korea.
Telephone: +82-2-22908338 Fax: +82-2-9720068
Received: August 27, 2018
Peer-review started: August 27, 2018
First decision: October 24, 2018
Revised: November 8, 2018
Accepted: November 13, 2018
Article in press: November 13, 2018
Published online: December 28, 2018
Research background

The receptor interacting protein kinase-3 (RIP3) inhibition in various non-alcoholic fatty liver disease (NAFLD) models has shown varied results. The underlying mechanism associated with these diverse outcomes is still not clear. The evaluation of necroptosis signaling molecules in NAFLD might provide a useful therapeutic target.

Research motivation

Previous studies report that in high fat (HF)-induced NAFLD, RIP3 deletion exacerbated fatty change, inflammation, fibrosis, and apoptosis. However, in the methionine choline deficient diet-induced NAFLD model, these changes were not observed. The reason for the varied results associated with RIP3 deletion in different NAFLD models is unknown.

Research objective

To validate the effects of RIP3 deletion in NAFLD and to clarify the mechanism of action.

Research methods

Wild-type and RIP3 knockout mice were fed HF and normal chow diets for 12 wk. The body weight was assessed weekly. After 12 wk, the liver and serum samples were analyzed for changes. Hematoxylin & eosin staining, NAFLD Activity Score evaluation, and triglyceride quantification were performed. The changes in very-low-density lipoproteins (VLDL) secretion and inflammation markers were recorded. Primary hepatocytes were evaluated for lipid contents. HepG2 cells and U937 cells were evaluated for changes in inflammatory markers.

Research results

Our results show that RIP3 deletion is associated with exacerbated hepatic lipid contents, suppressed VLDL secretion markers, and partially suppressed inflammation.

Research conclusion

In HF diet-induced NAFLD, RIP3 deletion is associated with increased hepatic steatosis and partially suppressed inflammation

Research perspective

Necroptosis signaling molecules, especially mixed lineage kinase domain-like proteins, should be further explored for its therapeutic potential in NAFLD.