The Vitamin D Receptor Regulates Glycerolipid and Phospholipid Metabolism in Human Hepatocytes

Abstract

The vitamin D receptor (VDR) must be relevant to liver lipid metabolism because VDR deficient mice are protected from hepatosteatosis. Therefore, our objective was to define the role of VDR on the overall lipid metabolism in human hepatocytes. We developed an adenoviral vector for human VDR and performed transcriptomic and metabolomic analyses of cultured human hepatocytes upon VDR activation by vitamin D (VitD). Twenty percent of the VDR responsive genes were related to lipid metabolism, including MOGAT1, LPGAT1, AGPAT2, and DGAT1 (glycerolipid metabolism); CDS1, PCTP, and MAT1A (phospholipid metabolism); and FATP2, SLC6A12, and AQP3 (uptake of fatty acids, betaine, and glycerol, respectively). They were rapidly induced (4–6 h) upon VDR activation by 10 nM VitD or 100 µM lithocholic acid (LCA). Most of these genes were also upregulated by VDR/VitD in mouse livers in vivo. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS) metabolomics demonstrated intracellular accumulation of triglycerides, with concomitant decreases in diglycerides and phosphatidates, at 8 and 24 h upon VDR activation. Significant alterations in phosphatidylcholines, increases in lyso-phosphatidylcholines and decreases in phosphatidylethanolamines and phosphatidylethanolamine plasmalogens were also observed. In conclusion, active VitD/VDR signaling in hepatocytes triggers an unanticipated coordinated gene response leading to triglyceride synthesis and to important perturbations in glycerolipids and phospholipids.

Impact of Vitamin D3 Deficiency on Phosphatidylcholine-/Ethanolamine, Plasmalogen-, Lyso-Phosphatidylcholine-/Ethanolamine, Carnitine- and Triacyl Glyceride-Homeostasis in Neuroblastoma Cells and Murine Brain

“…Additionally, they performed a transcriptomic analysis revealing that one fifth of the VDR responsive genes were related to lipidic pathways such as glycerolipid- and phospholipid metabolism or the uptake of fatty acids. In line with this, they reported a coordinated gene response of these genes due to VDR activation by calcitriol [ 14 ]. Moreover, we found the expression of genes known to play a role in lipid metabolism altered under mild to moderate vitamin D deficiency in a previous study [ 8 ].…”

“…Recent studies provide growing evidence for an important role of vitamin D 3 in the regulation of the lipid homeostasis [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. Most of the available studies analyzed this suggested link in the gastrointestinal system, kidney cells or tissue, but we lack information on such an association of vitamin D 3 and lipid metabolism in the brain.…”

“…In line with this, there is early evidence from the literature that 1,25-dihydroxyvitamin D 3 influences phospholipid composition in rat kidney samples [ 12 ] or chick intestine [ 13 ]. Recently, the relevance of the VDR for liver lipid metabolism was shown in human hepatocytes using transcriptomic and metabolomic analyses [ 14 ]. Additionally, in the intestine, VDR-mediated changes in lipid homeostasis were observed in mouse studies [ 15 , 16 ].…”

Vitamin D signaling inhibits HBV activity by directly targeting the HBV core promoter

“…Many host genes are involved in important stages of the HBV lifecycle, such as viral particle assembly and secretion ( 5 ). Vitamin D and its target receptors have been previously shown to extensively alter the cellular transcriptome and regulate numerous cellular processes ( 59 ). Vitamin D may affect crucial host genes involved in the HBV lifecycle.…”

Is vitamin D receptor a druggable target for non-alcoholic steatohepatitis?

“…It has been reported that VDR in hepatocytes might play a role in inhibiting bile acid synthesis, thus protecting liver from injury in cholestasis[ 47 ]. Transcriptomic and metabolomic analyses of hepatocytes transfected with human VDR have revealed that 20% of the VDR responsive genes were related to metabolism of lipids (including glycerolipids and phospholipids), uptake of fatty acids, betaine, and glycerol, suggesting a critical role of VDR in lipid metabolism in cultured hepatocytes[ 63 - 65 ]. In a global VDR-deficient mouse model, the livers were protected from steatosis, suggesting that VDR-mediated processes may contribute to NAFLD development[ 66 ], either due to enhanced lipid synthesis or reduced lipid turnover, or both.…”