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  • With regard to the clinical implications of


    With regard to the clinical implications of this aspect, an important recent study including data on NAFLD patients reported that hepatic expression of VDR was in fact up-regulated in fatty livers compared to non-steatotic controls [69]. Noteworthy, this up-regulation of VDR was more pronounced in patients with early NAFLD (i.e. steatosis) compared to patients with more progressed disease (i.e. non-alcoholic steatohepatitis, NASH), indicating a putative pro-steatogenic activity of VDR – especially in early NAFLD. The functional relevance of this finding was further supported by experiments in hepatoma APTSTAT3-9R and mice indicating a pro-steatogenic activity of VDR directly in hepatocytes [69]. These data were recently further validated in a follow-up study, in which the authors could also demonstrate that hepatic angiopoietin-like 8 (ANGPTL8) expression was elevated in NAFLD patients, and that its mRNA levels correlate with VDR mRNA as well as with the grade of liver steatosis [70]. Further mechanistic experiments from the same study suggested that ANGPTL8 is a novel target gene of VDR that promotes triglyceride accumulation in hepatocytes. On the other hand, an earlier paper by Barchetta et al. reported that VDR protein expression in the liver was rather decreased in a cohort of NASH patients and that VDR abundance was inversely associated with disease progression (assessed on the histopathological level as the NAFLD activity score, NAS) [71]. Together, these data indicate that the pathophysiological role of VDR in NAFLD may considerably differ between early and more progressed disease stages. Extending these findings, the results reported in our manuscript suggest that activation of VDR in the intestine can suppress Angptl4 as a further important metabolic regulator thereby exerting pro-adipogenic/steatogenic effects in distal tissues such as adipose tissue and liver. Together with the previous studies mentioned above, these findings warrant further preclinical studies testing the metabolic effects of (tissue-specific) pharmacological VDR agonist/antagonists in obesity and NAFLD to further evaluate the suitability of this signaling axis as a future therapeutic target in different disease stages. The following are the supplementary data related to this article.
    Author contributions DJ, JS, HMH and AG designed the study, planned the experiments and analyzed the data. JCF provided the transgenic mouse model, made important contributions to study design and data interpretation, provided the data shown in Fig. 7E and conducted the studies reported as Supplemental Table S2. DJ, DD, AKS, LG, JS, DK, CM and RNV performed experiments and analyzed the obtained data. DJ, HMH and AG drafted the manuscript. All authors reviewed and approved the final version of the manuscript.
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    Acknowledgements The authors thank Dr. Rinke Stienstra, Dr. Sander Kersten and Dr. Rudolf Zechner for stimulating discussion. This work was supported by grants of the Schweizerischer Nationalfonds SNF (310030_135548) and the Else Kröner-Fresenius-Stiftung EKFS (2014_A67) to AG. DJ was supported by a grant of the German Excellence Initiative to the Graduate School of Life Sciences, University of Würzburg. JCF was supported by a grant of the National Institute of Diabetes and Digestive and Kidney Diseases (award #DK54111). A part of this study has been published as conference abstracts at the International Liver Congress (EASL) and the Annual Meeting of the German Association for the Study of the Liver (GASL).
    Introduction Homeostatic signaling systems are conserved from insects to humans and are considered to interface with the mechanisms of neural plasticity in order to stabilize neural function [[1], [2], [3]]. These systems have been shown to control diverse cellular processes, including membrane excitability [2,4], postsynaptic neurotransmitter receptor abundance [5,6], and presynaptic neurotransmitter release [1].