Vitamin D: A Potential Star for Treating Chronic Pancreatitis

Abstract

Chronic pancreatitis (CP) is a chronic inflammatory and fibrotic disease of the pancreas. The incidence of CP is increasing worldwide but the effective therapies are lacking. Hence, it is necessary to identify economical and effective agents for the treatment of CP patients. Vitamin D (VD) and its analogues have been confirmed as pleiotropic regulators of cell proliferation, apoptosis, differentiation and autophagy. Clinical studies show that VD deficiency is prevalent in CP patients. However, the correlation between VD level and the risk of CP remains controversial. VD and its analogues have been demonstrated to inhibit pancreatic fibrosis by suppressing the activation of pancreatic stellate cells and the production of extracellular matrix. Limited clinical trials have shown that the supplement of VD can improve VD deficiency in patients with CP, suggesting a potential therapeutic value of VD in CP. However, the mechanisms by which VD and its analogues inhibit pancreatic fibrosis have not been fully elucidated. We are reviewing the current literature concerning the risk factors for developing CP, prevalence of VD deficiency in CP, mechanisms of VD action in PSC-mediated fibrogenesis during the development of CP and potential therapeutic applications of VD and its analogues in the treatment of CP.

Keywords: chronic pancreatitis; fibrosis; inflammation; vitamin D; vitamin D receptor.

FIGURE 1

The mechanism of PSC activation and the role of vitamin D in the process. When the pancreas is injured by ethanol, LPS or other factors, the damaged acinar cells can activate inflammatory cells to release pro-inflammatory cytokines which in turn activates quiescent PSCs to become activated phenotypes through paracrine stimuli. The activated PSCs can secrete cytokines to activate PSCs continuously through autocrine stimuli, resulting in pancreatic fibrosis. In addition, the activated PSCs can interact with other cell types, such as PCCs and immune cells, mediating the persistent inflammatory environment. Whereas, vitamin D can inhibit the activation and proliferation of PSCs, thereby reducing the synthesis of ECM. In addition, vitamin D play an anti-inflammatory and anti-fibrosis role via regulation of immune cells. LPS, lipopolysaccharide; PSCs, pancreatic stellate cells; ECM, extracellular matrix; PCCs, pancreatic cancer cells; CAFs, cancer-associated fibroblasts.

FIGURE 2

Vitamin D₃ metabolism and biological functions. In the canonical pathway, vitamin D₃ can be hydroxylated by CYP27A1/CYP2R1 and CYP27B1 to form 25(OH)D₃, and is then further hydroxylated to the active form 1,25(OH)₂D₃. 1,25(OH)₂D₃ can bind with VDR/RXR and translocate to the cell nucleus, where it binds to VDRE to regulate the transcription of target genes. Besides, 1,25(OH)₂D₃ may bind with a membrane-associated receptor to mediate non-genomic actions. In the non-canonical pathway, 7-DHC and vitamin D₃ are first hydroxylated by CYP11A1 and further hydroxylated by various cytochrome enzymes including CYP24A1, CYP27A1, CYP27B1, CYP2R1, CYP3A4, and CYP11A1 to form dihydroxy or trihydroxy metabolites. These bioactive metabolites selectively act on not only VDR, but also on alternative nuclear receptors such as AHR, RORs or LXRs and binds to AHREs, ROREs or LXREs to regulate the transcription of target genes. UVB, ultraviolet B; 7DHC, 7-dehydrocholesterol; VDBP, vitamin D-binding protein; PTH, parathyroid hormone; VDR, vitamin D receptor; RXR, retinoid X receptor; VDREs, VDR response elements; CDK1, cyclin dependent kinase 1; AHR, aryl hydrocarbon receptor; RORs, retinoic acid orphan receptors; LXRs, liver X receptors; AHREs, AHR response elements; ROREs, ROR response elements; LXREs, LXR response elements.