Intestinal vitamin D receptor modulates lipid metabolism, adipose tissue inflammation and liver steatosis in obese mice
Intestinal vitamin D receptor modulates lipid metabolism, adipose tissue inflammation and liver steatosis in obese mice
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DOI：
10.1016/j.bbadis.2019.03.007
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发表时间：
2019-06-01
影响因子：
6.2
通讯作者：
Geier, Andreas
中科院分区：
文献类型：
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作者：
Jahn, Daniel;Dorbath, Donata;Geier, Andreas
目的：维生素D缺乏症在肥胖人群和患有肥胖相关疾病（如2型糖尿病和脂肪肝）的患者中很常见，因此建议补充维生素D作为潜在的治疗选择。然而，维生素D-维生素D受体（VDR）轴对代谢紊乱的病理机制贡献在很大程度上是未知的。方法：我们使用全球VDR-/-小鼠和在VDR缺陷背景下重新表达精氨酸特异性人VDR转基因的小鼠分析了全球和肠道VDR信号在饮食诱导的肥胖（DIO）中的病理生理作用结果：Vdr-/-小鼠对DIO、脂肪肝及肝脏代谢性炎症有保护作用。此外，Vdr-/-小鼠显示脂肪组织脂蛋白脂酶（LPL）活性降低，从循环中收获甘油三酯的能力降低。有趣的是，所有这些表型在Vdr-/- hTg动物中部分逆转。这清楚地表明了基于精氨酸的VDR对全身脂质稳态的活性。仔细检查这一假设，我们确定了有效的LPL抑制剂血管生成素样4（Angpt 14）作为一种新的转录靶点的VDR.Conclusion：我们的研究表明，VDR介导的肠道和脂肪组织之间的代谢串扰，这显着有助于全身脂质稳态。这些结果对于使用肠道VDR作为肥胖和相关疾病的治疗靶点具有重要意义。
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 (Angpt14) 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.