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World J Gastroenterol. Oct 14, 2020; 26(38): 5812-5821
Published online Oct 14, 2020. doi: 10.3748/wjg.v26.i38.5812
Is vitamin D receptor a druggable target for non-alcoholic steatohepatitis?
Ying Cao, Xiang-Bing Shu, Zemin Yao, Guang Ji, Li Zhang
Ying Cao, Xiang-Bing Shu, Guang Ji, Li Zhang, Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
Xiang-Bing Shu, Department of Geratology, Baoshan Branch of Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201999, China
Zemin Yao, Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa K1H8M5, Ontario, Canada
Author contributions: Zhang L and Ji G contributed to the conceptualization; Cao Y, Shu XB and Zhang L contributed to the original draft preparation; Yao Z contributed to the review and editing; Cao Y and Shu XB contribute equally to this work.
Supported by the National Natural Science Foundation of China, No. 81774084 and 81804020; and Young Talent Promotion Project of Chinese Medicine Association, No. 2019-QNRC2-C04.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
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: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Li Zhang, MD, PhD, Senior Scientist, Institute of Digestive Diseases, Longhua Hospital, China-Canada Center of Research for Digestive Diseases, Shanghai University of Traditional Chinese Medicine, No. 725 South Wanping Road, Shanghai 200032, China. zhangli.hl@163.com
Received: August 7, 2020
Peer-review started: August 7, 2020
First decision: August 22, 2020
Revised: August 28, 2020
Accepted: September 8, 2020
Article in press: September 8, 2020
Published online: October 14, 2020
Abstract

Nonalcoholic steatohepatitis (NASH) is a progressed stage of non-alcoholic fatty liver disease, and available therapeutic strategies for NASH are limited. Vitamin D receptor (VDR) is proposed as a druggable target for NASH due to the discovery of vitamin D deficiency in NASH patients. To date, vitamin D supplementation has not consistently conferred expected therapeutic benefits, raising the question of whether VDR can serve as a proper drug target for NASH. It is known that VDR can interact with other ligands such as bile acids in addition to vitamin D, and its expression can be induced by fatty acids, and insulin. It has also been shown that while activation of VDR in hepatic macrophages and hepatic stellate cells resulted in attenuation of hepatic inflammation and fibrosis, activation of VDR in hepatocytes could accelerate lipid accumulation. Thus, the multiplicity of VDR ligands, together with the cell type-specificity of VDR activation, must be taken into consideration in assessing the validity of VDR being a potential druggable target for NASH treatment. To this end, we have evaluated the relationship between VDR activation and various contributing factors, such as gut microbiota, bile acid, fatty acids, and insulin, in addition to vitamin D, with an expectation that a potential drug might be identified that can elicit VDR activation in a tissue- and/or cell type-specific manner and therefore achieving therapeutic benefits in NASH.

Keywords: Vitamin D receptor, Non-alcoholic steatohepatitis, Vitamin D, Bile acids, Inflammation, Lipid metabolism

Core Tip: Vitamin D receptor (VDR) is a nuclear receptor and proposed as a druggable target for nonalcoholic steatohepatitis (NASH) due to the discovery of vitamin D deficiency in NASH patients. However, vitamin D supplementation has not consistently conferred expected therapeutic benefits. Actually, VDR can interact with other ligands such as bile acids in addition to vitamin D, and its expression can be induced by fatty acids, and insulin. Liver is an heterogenous organ, and VDR activation in hepatic macrophages and hepatic stellate cells results in attenuation of hepatic inflammation and fibrosis, whereas activation of VDR in hepatocytes can accelerate lipid accumulation. Thus, the multiplicity of VDR ligands, together with the cell type-specificity of VDR activation, must be taken into consideration in assessing the validity of VDR being a potential druggable target for NASH treatment.