8236 Hepatocyte Vitamin D Receptor (VDR) Regulates Liver Regeneration

Abstract Disclosure: J.E. Gunton: None. Harendran Elangovan [1], Rebecca A. Stokes [1], Jeremy Keane [1], Sarinder Chahal [1], Caroline Samer [1], Miguel Agoncillo [1], Josephine Yu [1], Jennifer Chen [1], Michael Downes 2, Ronald M. Evans 2, Christopher Liddle [1],2, Jenny E. Gunton [1] [1]Centre for Diabetes, Obesity and Endocrinology, The Westmead Institute for Medical Research, University of Sydney, Westmead, NSW, Australia 2 Salk Institute for Biological Studies, La Jolla, CA. USA Background: Vitamin D signals through the vitamin D receptor (VDR) to induce its end-organ effects. Hepatic stellate cells control development of liver fibrosis in response to stressors and vitamin D signaling decreases fibrogenesis. VDR expression in hepatocytes, however, is low in healthy liver, and the role of VDR in hepatocyte proliferation is unclear. Methods: In these studies, hepatocyte-VDR null mice (hVDR) were used to assess the role of VDR and vitamin D signaling in hepatic regeneration. Mice underwent 2/3 partial hepatectomy and liver regeneration and function were studied. Results: hVDR mice had impaired liver regeneration with impaired hepatocyte proliferation. This was associated with significant differential changes in bile salts. Notably, mice lacking hepatocyte VDR had significant increases in expression of conjugated bile acids after partial hepatectomy, consistent with failure to normalize hepatic function by the 14-day time point tested. CDCA (chenodeoxycholate) is an FXR ligand, which was increased after surgery in controls but not in hVDR mice. FXR signaling is important for hepatocyte proliferation. Real-time PCR of hVDR and control livers showed significant changes in expression of cell cycle genes including cyclins D1 and E1 and cyclin-dependent kinase 2. Gene expression profiling of hepatocytes treated with vitamin D or control showed regulation of groups of genes involved in liver proliferation, hepatitis, liver hyperplasia / hyperproliferation and liver necrosis / cell death. Conclusions: Together these studies demonstrate an important functional role for VDR in hepatocytes during liver regeneration. Combined with the known profibrotic effects of impaired VDR signaling in stellate cells, these studies provide a mechanism whereby vitamin D deficiency would both reduce hepatocyte proliferation and permit fibrosis, leading to significant liver compromise. Presentation: 6/2/2024