Hepatocyte vitamin D receptor regulates lipid metabolism and mediates experimental diet-induced steatosis
Hepatocyte vitamin D receptor regulates lipid metabolism and mediates experimental diet-induced steatosis
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DOI：
10.1016/j.jhep.2016.05.031
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发表时间：
2016-10-01
影响因子：
25.7
通讯作者：
Jover, Ramiro
中科院分区：
文献类型：
--
作者：
Bozic, Milica;Guzman, Carla;Jover, Ramiro
背景与目的：非酒精性脂肪性肝病（NAFLD）的发病机制和进展尚不完全清楚。几种核受体在肝脏脂质代谢中起作用，并可促进肝骨化病，但维生素D受体（VDR）在NAFLD中的可能作用尚未研究。方法：研究高脂饮食中载脂蛋白E敲除（apoE(-/-)）小鼠、蛋氨酸和胆碱缺乏饮食的野生型小鼠以及NAFLD合并肝纤维化和非酒精性脂肪性肝炎患者肝脏VDR的表达。在apoE（-/-）小鼠中，通过删除VDR或特殊醇处理来评估VDR的相关性，在人HepG2细胞中，通过转染VDR或沉默来评估VDR的相关性。在用硫乙酰胺处理的VDR敲除小鼠（VDR-/-）中，也确定了VDR在纤维化中的作用。结果：肝VDR在两种NAFLD小鼠模型和肝纤维化患者中均有明显的表达，但在非酒精性脂肪性肝炎中表达降低。在高脂肪饮食喂养的apoE（-/-）小鼠中，VDR缺失对脂肪肝、血脂异常和胰岛素抵抗有保护作用，并导致牛磺酸偶联胆胆酸减少，但不影响硫乙酰胺引起的纤维化。apoE(-/-)VDR（-/-）小鼠肝脏CD36、DGAT2、C/EBP α和FGF21基因表达降低，PNPLA2、LIPINI和PGC1 α表达升高。对高脂饮食的apoE（-/-）小鼠用特立糖醇治疗对脂肪变性和基因表达有适度的相反作用。最后，当VDR在HepG2细胞中过表达或沉默时，这组基因表现出一致的反应。结论：NAFLD诱导的肝细胞VDR调节关键的肝脂代谢基因，促进高脂饮食相关的肝脂肪变性。治疗性抑制肝脏VDR可能逆转早期NAFLD的脂肪变性。摘要：当小鼠和人类发生非酒精性脂肪肝疾病时，其肝脏中维生素D受体的含量在早期被诱导。如果维生素D受体基因被删除，肝脏脂质代谢就会改变，老鼠的肝脏就不会积累脂肪。我们得出结论，维生素D受体可能会导致高脂肪饮食导致的脂肪肝疾病。(C) 2016欧洲肝脏研究协会。Elsevier B.V.版权所有。
Background & Aims: The pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD) is still incompletely understood. Several nuclear receptors play a role in liver lipid metabolism and can promote hepatosteatosis, but the possible role of vitamin D receptor (VDR) in NAFLD has not been investigated.Methods: The expression of liver VDR was investigated in apolipoprotein E knockout (apoE(-/-)) mice on a high fat diet, in wild-type mice on methionine and choline deficient diet and in NAFLD patients with hepatosteatosis and non-alcoholic steatohepatitis. The relevance of VDR was assessed in apoE(-/-) mice by deletion of VDR or paricalcitol treatment and in human HepG2 cells by VDR transfection or silencing. The role of VDR in fibrosis was also determined in VDR knockout mice (VDR-/-) treated with thioacetamide.Results: Expression of liver VDR was markedly induced in two mouse models of NAFLD, as well as in patients with hepatosteatosis, but decreased in non-alcoholic steatohepatitis. VDR deletion in high fat diet-fed apoE(-/-) mice protected against fatty liver, dyslipidemia and insulin resistance, and caused a decrease in taurine-conjugated bile acids, but did not influence fibrosis by thioacetamide. apoE(-/-)VDR(-/-) mouse livers showed decreased gene expression of CD36, DGAT2, C/EBP alpha and FGF21, and increased expression of PNPLA2, LIPINI and PGC1 alpha. Treatment of apoE(-/-) mice on high fat diet with paricalcitol had modest opposite effects on steatosis and gene expression. Finally, this set of genes showed concordant responses when VDR was overexpressed or silenced in HepG2 cells.Conclusions: Induced hepatocyte VDR in NAFLD regulates key hepatic lipid metabolism genes and promotes high fat diet-associated liver steatosis. Therapeutic inhibition of liver VDR may reverse steatosis in early NAFLD.Lay summary: The amount of vitamin D receptor is induced early in the livers of mice and humans when they develop nonalcoholic fatty liver disease. If the gene for the vitamin D receptor is deleted, hepatic lipid metabolism changes and mice do not accumulate fat in the liver. We conclude that the vitamin D receptor can contribute to the fatty liver disease promoted by a high fat diet. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.