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1.
Biochim Biophys Acta Mol Basis Dis ; 1865(6): 1567-1578, 2019 06 01.
Article in English | MEDLINE | ID: mdl-30905785

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.


Subject(s)
Angiopoietin-Like Protein 4/genetics , Fatty Liver/genetics , Intestinal Mucosa/metabolism , Lipoprotein Lipase/genetics , Liver/metabolism , Receptors, Calcitriol/genetics , Adipose Tissue/metabolism , Adipose Tissue/pathology , Adult , Aged , Angiopoietin-Like Protein 4/metabolism , Animals , Cohort Studies , Fatty Liver/metabolism , Fatty Liver/pathology , Female , Gene Expression Regulation , Humans , Inflammation , Intestinal Mucosa/pathology , Lipid Metabolism/genetics , Lipoprotein Lipase/antagonists & inhibitors , Lipoprotein Lipase/metabolism , Liver/pathology , Male , Mice , Mice, Obese , Mice, Transgenic , Middle Aged , Receptors, Calcitriol/deficiency , Signal Transduction , Transcription, Genetic , Transgenes , Triglycerides/metabolism
2.
Nutrients ; 11(1)2019 Jan 03.
Article in English | MEDLINE | ID: mdl-30609782

ABSTRACT

Serum vitamin D levels negatively correlate with obesity and associated disorders such as non-alcoholic steatohepatitis (NASH). However, the mechanisms linking low vitamin D (VD) status to disease progression are not completely understood. In this study, we analyzed the effect of VD treatment on NASH in mice. C57BL6/J mice were fed a high-fat/high-sugar diet (HFSD) containing low amounts of VD for 16 weeks to induce obesity, NASH and liver fibrosis. The effects of preventive and interventional VD treatment were studied on the level of liver histology and hepatic/intestinal gene expression. Interestingly, preventive and to a lesser extent also interventional VD treatment resulted in improvements of liver histology. This included a significant decrease of steatosis, a trend towards lower non-alcoholic fatty liver disease (NAFLD) activity score and a slight non-significant decrease of fibrosis in the preventive treatment group. In line with these changes, preventive VD treatment reduced the hepatic expression of lipogenic, inflammatory and pro-fibrotic genes. Notably, these beneficial effects occurred in conjunction with a reduction of intestinal inflammation. Together, our observations suggest that timely initiation of VD supplementation (preventive vs. interventional) is a critical determinant of treatment outcome in NASH. In the applied animal model, the improvements of liver histology occurred in conjunction with reduced inflammation in the gut, suggesting a potential relevance of vitamin D as a therapeutic agent acting on the gut⁻liver axis.


Subject(s)
Diet, High-Fat/adverse effects , Dietary Carbohydrates/administration & dosage , Obesity/chemically induced , Vitamin D/therapeutic use , Animals , Blood Glucose/drug effects , Body Composition , Body Weight/drug effects , Cholesterol 7-alpha-Hydroxylase/genetics , Cholesterol 7-alpha-Hydroxylase/metabolism , Fibroblast Growth Factors/genetics , Fibroblast Growth Factors/metabolism , Gene Expression Regulation/drug effects , Glucose Intolerance/drug therapy , Intestines/drug effects , Intestines/physiology , Liver/anatomy & histology , Liver/drug effects , Mice , Mice, Inbred C57BL , Non-alcoholic Fatty Liver Disease/metabolism , Steroid 12-alpha-Hydroxylase/genetics , Steroid 12-alpha-Hydroxylase/metabolism , Up-Regulation/drug effects
3.
Biochim Biophys Acta ; 1859(2): 381-92, 2016 Feb.
Article in English | MEDLINE | ID: mdl-26723851

ABSTRACT

Fibroblast growth factor 19 (FGF19) is a gut-derived hormone that controls bile acid (BA), carbohydrate and lipid metabolism. Whereas strong evidence supports a key role of BAs and farnesoid X receptor (FXR) for the control of FGF19 expression, information on other regulators is limited. In mice, FGF15 expression (ortholog of human FGF19) is induced by vitamin A (VitA) in an FXR-dependent manner. However, the significance of this finding for human FGF19 is currently unclear. Here, we demonstrate that VitA derivatives induce FGF19 in human intestinal cell lines by a direct transcriptional mechanism. In contrast to mouse FGF15, however, this direct regulation is not dependent on FXR but mediated by retinoic acid receptors (RARs) and their interaction with a novel DR-5 element in the human FGF19 gene. In addition to this direct effect, VitA derivatives impacted on the BA-mediated control of FGF19 by regulation of FXR protein levels. In conclusion, VitA regulates human FGF19 expression through FXR-dependent and -independent pathways. Moreover, we suggest that considerable mechanistic differences exist between humans and mice with regard to the nuclear receptors controlling the VitA-FGF15/19 axis. These findings may implicate a clinical relevance of RAR-activating VitA derivatives for the regulation of FGF19 levels in humans.


Subject(s)
Fibroblast Growth Factors/genetics , Receptors, Cytoplasmic and Nuclear/genetics , Transcription, Genetic , Vitamin A/metabolism , Animals , Bile Acids and Salts/genetics , Bile Acids and Salts/metabolism , Cell Line , Fibroblast Growth Factors/biosynthesis , Gene Expression Regulation , Humans , Intestinal Mucosa/metabolism , Intestines/cytology , Lipid Metabolism/genetics , Mice , Receptors, Cytoplasmic and Nuclear/metabolism , Receptors, Retinoic Acid/genetics , Receptors, Retinoic Acid/metabolism , Signal Transduction , Vitamin A/analogs & derivatives , Vitamin A/genetics
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