Is vitamin D receptor a druggable target for non-alcoholic steatohepatitis?

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.