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      A Randomized, Controlled Trial of Vitamin D Supplementation on Cardiovascular Risk Factors, Hormones, and Liver Markers in Women with Polycystic Ovary Syndrome

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          Abstract

          Polycystic ovary syndrome (PCOS) increases the risk of metabolic syndrome and non-alcoholic-fatty-liver disease (NAFLD). Vitamin D supplementation may exert positive effects on liver biochemistry in patients with NAFLD; however, its effects on PCOS are unknown. This randomized, double-blind, placebo-controlled study explored the effect of vitamin D supplementation on cardiovascular risk factors (high-sensitivity C-reactive protein ( hs-CRP), weight, body mass index (BMI), lipid profile, glucose levels, insulin levels, the homeostatic model assessment-insulin resistance (HOMA-IR), hormones (free androgen index (FAI), testosterone, sex hormone binding globulin (SHBG), and liver markers (alanine aminotransferase (ALT), hyaluronic acid (HA), N-terminal pro-peptide of type III procollagen (PIIINP), tissue inhibitor of metallo-proteinases-1 (TIMP-1), and the enhanced liver fibrosis (ELF) score). Forty women with PCOS were recruited and randomized to vitamin D (3200 IU) or placebo daily for 3 months. All outcomes were measured at baseline and 3 months follow-up (FU). Greater increases in vitamin D levels were shown in the supplementation group (vitamin D, baseline: 25.6 ± 11.4 nmol/L, FU: 90.4 ± 19.5 nmol/L vs. placebo, baseline: 30.9 ± 11.1 nmol/L, FU: 47.6 ± 20.5 nmol/L, p < 0.001). Between groups comparisons (% baseline change) revealed significant differences in ALT ( p = 0.042) and a weak effect indicating a greater reduction in the HOMA-IR in the vitamin D group ( p = 0.051). No further between group differences were seen in other cardiovascular risk factor, liver markers, or hormones. This study supports beneficial effects of vitamin D supplementation on liver markers and modest improvements in insulin sensitivity in vitamin D deficient women with PCOS.

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          EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease.

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            A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response.

            Liver fibrosis is a reversible wound-healing response involving TGFβ1/SMAD activation of hepatic stellate cells (HSCs). It results from excessive deposition of extracellular matrix components and can lead to impairment of liver function. Here, we show that vitamin D receptor (VDR) ligands inhibit HSC activation by TGFβ1 and abrogate liver fibrosis, whereas Vdr knockout mice spontaneously develop hepatic fibrosis. Mechanistically, we show that TGFβ1 signaling causes a redistribution of genome-wide VDR-binding sites (VDR cistrome) in HSCs and facilitates VDR binding at SMAD3 profibrotic target genes via TGFβ1-dependent chromatin remodeling. In the presence of VDR ligands, VDR binding to the coregulated genes reduces SMAD3 occupancy at these sites, inhibiting fibrosis. These results reveal an intersecting VDR/SMAD genomic circuit that regulates hepatic fibrogenesis and define a role for VDR as an endocrine checkpoint to modulate the wound-healing response in liver. Furthermore, the findings suggest VDR ligands as a potential therapy for liver fibrosis. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Vitamin D inhibits proliferation and profibrotic marker expression in hepatic stellate cells and decreases thioacetamide-induced liver fibrosis in rats.

              Hepatic stellate cells (HSCs) are key participants in liver fibrosis development. 1,25(OH)(2)D(3), the active form of vitamin D, has antiproliferative properties and antifibrotic potential, as well as a role in extracellular matrix and matrix metalloproteinase (MMP) regulation in renal and lung fibrosis. Little is known about the role of 1,25(OH)(2)D(3) in liver and its involvement in liver fibrosis. Therefore, we investigated the antiproliferative and antifibrotic effects of 1,25(OH)(2)D(3) in primary cultured HSCs and in a rat model of liver fibrosis induced by thioacetamide (TAA). Primary HSCs were isolated from rats' livers and treated with 1,25(OH)(2)D(3). Proliferation was examined by bromodeoxyuridine. Vitamin D receptor (VDR) expression and several fibrotic markers were detected by western blot analysis and real-time PCR. Collagen Iα1 and MMP-9 promoter activity were measured by luciferase assay. MMP-9 enzymatic activity was investigated by zymography. VDR silencing was performed by sh-RNA. An in vivo study was performed on TAA-induced liver fibrosis model in rats treated with or without 1,25(OH)(2)D(3). The fibrotic score and collagen deposition were determined by Masson and by Sirius red staining. While VDR was highly expressed in quiescent HSCs, its expression decreased up to 40% during activation. Addition of 1,25(OH)(2)D(3) to activated HSCs stimulated VDR expression. 1,25(OH)(2)D(3) suppressed HSC proliferation and cyclin D1 expression by ~50% and tissue inhibitor of metalloproteinase 1 (TIMP-1) by 60% and led to a 40% downregulation of collagen Iα1 expression. Moreover, 1,25(OH)(2)D(3) increased MMP-9 activity by 30%. Silencing VDR by sh-RNA demonstrated that suppression of cyclin D1 and collagen Iα1 protein expression was VDR dependent. Treatment with 1,25(OH)(2)D(3) significantly reduced extracellular matrix deposition and lowered the fibrotic score in TAA-induced liver fibrosis. 1,25(OH)(2)D(3) has antiproliferative and antifibrotic effects on liver fibrosis in in vitro and in vivo models and may be considered as having potential therapeutic value.
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                Author and article information

                Journal
                Nutrients
                Nutrients
                nutrients
                Nutrients
                MDPI
                2072-6643
                17 January 2019
                January 2019
                : 11
                : 1
                : 188
                Affiliations
                [1 ]Department of Academic Diabetes, Endocrinology and Metabolism, Hull York Medical School, University of Hull, Hull HU3 2JZ, UK; Zeeshan.Javed@ 123456pkli.org.pk (Z.J.); m.papageorgiou@ 123456hull.ac.uk (M.P.); harshaldeshmukh@ 123456nhs.net (H.D.)
                [2 ]Department of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology, and Immunology, Medical University of Vienna, Vienna 1090, Austria
                [3 ]Department of Pathology, Sidra Medical and Research Centre, Doha PO Box 26999, Qatar; ekilpatrick@ 123456sidra.org
                [4 ]Gastroenterology Research Department, Hull Royal Infirmary, Hull HU3 2JZ, UK; Vincent.mann@ 123456hey.nhs.uk (V.M.); l.corless@ 123456hull.ac.uk (L.C.); George.Abouda@ 123456hey.nhs.uk (G.A.)
                [5 ]Hull York Medical School, University of Hull, Hull HU3 2JZ, UK; A.rigby@ 123456hull.ac.uk
                [6 ]Weill Cornell Medical College Qatar, Education City, Doha PO Box 24144, Qatar; sla2002@ 123456qatar-med.cornell.edu
                Author notes
                [* ]Correspondence: Thozhukat.Sathyapalan@ 123456hyms.ac.uk ; Tel.: +44-148-267-5312
                Author information
                https://orcid.org/0000-0002-8974-2371
                https://orcid.org/0000-0002-9943-6976
                https://orcid.org/0000-0002-5887-7257
                https://orcid.org/0000-0003-3544-2231
                Article
                nutrients-11-00188
                10.3390/nu11010188
                6356309
                30658483
                0549a093-fb10-470d-bbaa-aef1240a2107
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 14 December 2018
                : 15 January 2019
                Categories
                Article

                Nutrition & Dietetics
                polycystic ovary syndrome,vitamin d,liver markers,cardiovascular risk factors,hormones

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