Liver vitamin D receptor, CYP2R1, and CYP27A1 expression: relationship with liver histology and vitamin D3 levels in patients with nonalcoholic steatohepatitis or hepatitis C virus

Abstract

Evidence suggests an association between low serum 25-hydroxy-vitamin D 3 [25(OH)D 3 ] levels and the presence and prognosis of liver disease. Vitamin D receptor (VDR) has been widely detected in the liver, but its expression in the course of liver disease has never been investigated. We evaluated the hepatic expression of VDR along with that of vitamin D 25-hydroxylases in patients with nonalcoholic steatohepatitis (NASH) or chronic hepatitis C (CHC) and its relationship with hepatic histological features and serum 25(OH)D 3 levels. We evaluated 61 patients (25 NASH and 36 CHC) who had undergone liver biopsy for clinical purposes and 20 subjects without liver disease. Serum 25(OH)D 3 was measured via colorimetric assay. Expression of VDR, CYP2R1, and CYP27A1 was evaluated via immunohistochemistry in hepatocytes, cholangiocytes, and liver inflammatory cells. Parenchymal and inflammatory cells from liver biopsies of patients with NASH and CHC expressed VDR, CYP2R1, and CYP27A1. In NASH patients, VDR expression on cholangiocytes was inversely correlated with steatosis severity (P < 0.02), lobular inflammation (P < 0.01), and nonalcoholic fatty liver disease score (P < 0.03). Moreover, expression of CYP2R1 in hepatocytes correlated strongly with VDR positivity on liver inflammatory cells. In CHC subjects, fibrosis stage was associated with low hepatic CYP27A1 expression, whereas portal inflammation was significantly higher in patients with VDR-negative inflammatory cells (P < 0.009) and low VDR expression in hepatocytes (P < 0.03). Conclusion: VDR is widely expressed in the liver and inflammatory cells of chronic liver disease patients and its expression is negatively associated with the severity of liver histology in both NASH and CHC patients. These data suggest that vitamin D/VDR system may play a role in the progression of metabolic and viral chronic liver damage. (HEPATOLOGY 2012;56:2180-2187 R ecent studies have suggested a direct association between low serum 25-hydroxy-vitamin From the

Vitamin D levels and liver histological alterations in children with nonalcoholic fatty liver disease

“…This extrarenal production of 1,25(OH) 2 VD, together with a wide VDR availability, allows a local paracrine/autocrine regulation. In fact, 1,25(OH) 2 VD controls the expression of many genes, playing a key role in cell proliferation, differentiation, inflammation, and immunity (24,25).…”

“…In the liver, VDR is expressed in cholangiocytes, and this expression has been shown to be inversely associated with steatosis severity, lobular inflammation, and NAFLD score in adult patients with NASH (25). Moreover, both animal and human data suggest that 1,25(OH) 2 VD may have anti-fibrogenic effects (25,26).…”

“…Moreover, both animal and human data suggest that 1,25(OH) 2 VD may have anti-fibrogenic effects (25,26). Selected VDR polymorphisms have been reported to be associated with primary biliary cirrhosis (27).…”

Recent advances in dietary supplementation, in treating non-alcoholic fatty liver disease

“…In humans, vitamin D deficiency has been correlated with a more severe NAFLD activity score and hepatic fibrosis [78] , perhaps owing to the greater oxidative stress resulting from vitamin D deficiency [79] . Hepatic expression of vitamin D receptors, CYP2R1 and CYP 27A1, negatively correlates with the severity of steatosis, inflammation, and NAFLD scores in patients with this disease [80] . A recent study found a significant association between NAFLD and low serum vitamin D levels [81] ; this relationship remained significant even after adjustments were made for the presence of other metabolic syndrome features.…”

Non-alcoholic fatty liver disease: an emerging driving force in chronic kidney disease

“…AMPK, 5' adenosine monophosphate-activated protein kinase; Ask-1, apoptosis signal-regulating kinase 1 (Ask-1 is also known as mitogen-activated protein kinase kinase kinase 5 (MAP3K5)); CCL2 chemokine (C-C motif) ligand 2 (CCL2 is also referred to as monocyte chemoattractant protein 1 (MCP1)); CCR, chemokine receptor; FGF-21, fibroblast growth factor-21; JNK, C-Jun-Nterminal kinase; mTOR, mechanistic target of rapamycin/ mammalian target of rapamycin; PPARs, peroxisome activated proliferated receptors α, γ and δ; NF-kB, nuclear factor-kB; Nrf 2, nuclear factor (erythroid-derived 2)-like 2; FXR, farnesoid X receptor; SREBPs, sterol regulatory element binding protein. Hepatic inflammation and fibrosis 79,80 .…”