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Hepatic actions of vitamin D receptor ligands: a sunshine option for chronic liver disease?

The vitamin D receptor (VDR) belongs to the nuclear hormone receptor (NHR) superfamily and has been recognized as the primary mediator of the physiological actions of the active form of vitamin D, 1, alpha, 25 dihydroxy-vitamin D3 [1,25-(OH)2D3] or calcitriol, and its synthetic analogs[1]. Akin to classical nuclear hormone receptors, VDR functions as a ligand-dependent transcription factor that binds to vitamin D response elements (VDREs) within the chromatin as a heterodimer with its obligate partner, retinoid X receptor (RXR)[1]. Activation of VDR via its cognate ligand alters the expression of a network of genes involved in both calcium/phosphorus homeostasis and mineral metabolism[1]. Consistent with the biological role of vitamin D signaling, both VDR knockout and vitamin D-deficient mice have been shown to develop hypocalcaemia, rickets and hyperparathyroidism[1], re-capitulating the phenotypes of these vitamin D deficient human diseases. Thus, both biochemical and genetic evidence not only support VDR as a master regulator of skeletal health but also suggest potential therapeutic effects of VDR ligands in human diseases. Indeed, vitamin D is used therapeutically for the treatment of rickets, secondary hyperparathyroidism and osteoporosis[1]. Clinical interest in VDR ligands as a therapeutic modality has been further spurred by the observation that VDR is expressed in virtually all organs and a diverse range of cell types[1,2]. In this regard, studies over the last two decades have led to an appreciation of the multifaceted roles of VDR in mediating homeostatic effects across non-skeletal tissues and raised the possibility of using VDR ligands to manage a broad spectrum of diseases including, but not limited to, metabolic syndrome, cardiovascular diseases, auto-immune diseases, skin and muscle disorders, and certain types of cancer[2]. However, it is intriguing that the liver, a pivotal organ in many aspects of metabolism and energy homeostasis, appeared devoid of vitamin D/VDR functionality [3,4].