Several authors have demonstrated that lithocholic acid is a physiologic ligand of VDR33 and modulates bile acid detoxification. Han et al.22 identified VDR protein and messenger RNA in primary cultures of human hepatocytes and demonstrated that this receptor plays a critical role in the inhibition of the synthesis

of bile Obeticholic Acid mw acids, protecting the hepatocytes from cholestatic injury. VDR can be activated by either lithocholic acid acetate or 1α,25(OH)2D3 and exerts its activity through the transcriptional inhibition of CYP7A1, the initial and rate-limiting enzyme of bile acid synthesis, reducing the synthesis of bile acids in human hepatocytes.21 Interestingly, in beta-catenin assay NASH patients, we found that VDR expression on cholangiocytes was inversely associated with NAS, suggesting a possible role of VDR, expressed on biliary cells, in modulating the inflammatory process in course of liver disease. Studies in animal models and in patients with biliary disorders and CHC have shown that the ductal epithelium can express several profibrogenic and chemotactic proteins, the latter capable of attracting

and activating inflammatory and fibrogenic cells.34-36 In this study, we demonstrated that liver expression of both CYP2R1 and CYP27A1 is preserved in NASH patients. This observation may question the hypothesis of a loss of hydroxylation capacity of hepatocytes in the course of NASH. Conversely, low 25(OH)D3 levels could favor, along with known risk factors, the intrahepatic accumulation of lipids, insulin resistance, progressive hepatic steatosis, and the development of steatohepatitis. Overall, the present study suggests that vitamin D may influence the inflammatory response to chronic liver injury both

in NASH and in CHC patients by means of its specific VDR, widely expressed on hepatic cell lines. In addition to the immunomodulator MCE and antiproliferative activities on inflammatory cells, it is plausible to hypothesize that vitamin D exerts its action on cholangiocytes, in which the expression of VDR is particularly pronounced. Low hepatic VDR expression, closely associated with more severe liver histology in this study, could represent the primary event leading to progression of hepatitis. VDR polymorphisms have been investigated in the context of chronic liver diseases such as primary biliary cirrhosis and autoimmune hepatitis, where they seem to contribute to the risk of liver disease development.16, 17 Indeed, because serum 25(OH)D3 levels in our population of NASH patients are comparable to those observed in obese subjects without liver disease, it is plausible that VDR polymorphisms affecting liver VDR expression may play a role in the development and progression of NASH independently from serum vitamin D status.