Intestinal vitamin D receptor modulates lipid metabolism, adipose tissue inflammation and liver steatosis in obese mice.

Abstract

OBJECTIVE:

Hypovitaminosis D is common in the obese population and patients suffering from obesity-associated disorders such as type 2 diabetes and fatty liver disease, resulting in suggestions for vitamin D supplementation as a potential therapeutic option. However, the pathomechanistic contribution of the vitamin D-vitamin D receptor (VDR) axis to metabolic disorders is largely unknown.

METHODS:

We analyzed the pathophysiological role of global and intestinal VDR signaling in diet-induced obesity (DIO) using global Vdr-/- mice and mice re-expressing an intestine-specific human VDR transgene in the Vdr deficient background (Vdr-/- hTg).

RESULTS:

Vdr-/- mice were protected from DIO, hepatosteatosis and metabolic inflammation in adipose tissue and liver. Furthermore, Vdr-/- mice displayed a decreased adipose tissue lipoprotein lipase (LPL) activity and a reduced capacity to harvest triglycerides from the circulation. Intriguingly, all these phenotypes were partially reversed in Vdr-/- hTg animals. This clearly suggested an intestine-based VDR activity on systemic lipid homeostasis. Scrutinizing this hypothesis, we identified the potent LPL inhibitor angiopoietin-like 4 (Angptl4) as a novel transcriptional target of VDR.

CONCLUSION:

Our study suggests a VDR-mediated metabolic cross-talk between gut and adipose tissue, which significantly contributes to systemic lipid homeostasis. These results have important implications for use of the intestinal VDR as a therapeutic target for obesity and associated disorders.

• Authors: Daniel Jahn, Donata Dorbath, Anne-Kristin Schilling, Lisa Gildein, Chantal Meier, Raphael N Vuille-Dit-Bille, Johannes Schmitt, Daniel Kraus, James C Fleet, Heike M Hermanns, Andreas Geier
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1865 Issue 6 Pg. 1567-1578 (06 01 2019) ISSN: 1879-260X [Electronic] Netherlands
• PMID: 30905785 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Angiopoietin-Like Protein 4
• Receptors, Calcitriol
• Triglycerides
• VDR protein, human
• Lipoprotein Lipase

Topics

• Adipose Tissue (metabolism, pathology)
• Adult
• Aged
• Angiopoietin-Like Protein 4 (genetics, metabolism)
• Animals
• Cohort Studies
• Fatty Liver (genetics, metabolism, pathology)
• Female
• Gene Expression Regulation
• Humans
• Inflammation
• Intestinal Mucosa (metabolism, pathology)
• Lipid Metabolism (genetics)
• Lipoprotein Lipase (antagonists & inhibitors, genetics, metabolism)
• Liver (metabolism, pathology)
• Male
• Mice
• Mice, Obese
• Mice, Transgenic
• Middle Aged
• Receptors, Calcitriol (deficiency, genetics)
• Signal Transduction
• Transcription, Genetic
• Transgenes
• Triglycerides (metabolism)