Phytosterols promote liver injury and Kupffer cell activation in parenteral nutrition-associated liver disease.
Phytosterols promote liver injury and Kupffer cell activation in parenteral nutrition-associated liver disease.
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DOI：
10.1126/scitranslmed.3006898
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发表时间：
2013-10-09
影响因子：
17.1
通讯作者：
Sokol RJ
中科院分区：
文献类型：
--
作者：
El Kasmi KC;Anderson AL;Devereaux MW;Vue PM;Zhang W;Setchell KD;Karpen SJ;Sokol RJ
肠外营养相关性肝病(PNALD)是不耐受肠内喂养的婴儿PN的严重并发症，尤其是后天或先天性肠道疾病的婴儿。然而，PNALD背后的机制还知之甚少。有人认为，PN溶液中大豆油(SO)脂肪乳剂中的一种成分，如植物甾醇(植物甾醇)可能是PNALD的原因，而使用以鱼油(FO)为基础的脂肪乳剂可能具有保护作用。我们使用了PNALD的小鼠模型，结合PN输注和肠道损伤，证明了基于SO的PN溶液会导致肝脏损伤和肝脏巨噬细胞激活，而以FO为基础的或不含所有脂质的PN溶液可以阻止这些过程。我们进一步证明，在这个模型中，SO脂肪乳剂中的一个因子豆甾醇可以促进胆汁淤积、肝脏损伤和肝巨噬细胞的激活，并且这种作用可能是通过拮抗核受体FXR和LXR而抑制小管胆汁转运蛋白(Abcb11/BSEP，Abcc2/MRP2)的表达，以及未能上调肝脏类固醇出口因子(Abcg5/G8/ABCG5/8)来实现的。这项研究提供了实验证据，证明脂肪乳剂中的植物类固醇是导致PNALD的主要因素，并且植物类固醇的缺乏或减少是接受基于FO的PN或脂肪最小化PN治疗的婴儿保护肝脏的机制之一。因此，修改PN液中的脂质成分是降低PNALD发生率和严重程度的一种有前途的策略。
Parenteral nutrition–associated liver disease (PNALD) is a serious complication of PN in infants who do not tolerate enteral feedings, especially those with acquired or congenital intestinal diseases. Yet, the mechanisms underlying PNALD are poorly understood. It has been suggested that a component of soy oil (SO) lipid emulsions in PN solutions, such as plant sterols (phytosterols), may be responsible for PNALD, and that use of fish oil (FO)–based lipid emulsions may be protective. We used a mouse model of PNALD combining PN infusion with intestinal injury to demonstrate that SO-based PN solution causes liver damage and hepatic macrophage activation and that PN solutions that are FO-based or devoid of all lipids prevent these processes. We have furthermore demonstrated that a factor in the SO lipid emulsions, stigmasterol, promotes cholestasis, liver injury, and liver macrophage activation in this model and that this effect may be mediated through suppression of canalicular bile transporter expression (Abcb11/BSEP, Abcc2/MRP2) via antagonism of the nuclear receptors Fxr and Lxr, and failure of up-regulation of the hepatic sterol exporters (Abcg5/g8/ABCG5/8). This study provides experimental evidence that plant sterols in lipid emulsions are a major factor responsible for PNALD and that the absence or reduction of plant sterols is one of the mechanisms for hepatic protection in infants receiving FO-based PN or lipid minimization PN treatment. Modification of lipid constituents in PN solutions is thus a promising strategy to reduce incidence and severity of PNALD.
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影响因子：
29.4
作者：
CLAYTON, PT;BOWRON, A;MILLA, PJ
通讯作者：
MILLA, PJ
影响因子：
3.1
作者：
Hallikainen, Maarit;Huikko, Laura;Gylling, Helena
通讯作者：
Gylling, Helena
影响因子：
4.2
作者：
Kosters A;Karpen SJ
通讯作者：
Karpen SJ
DOI：
10.1097/mpg.0b013e318182c8f6
发表时间：
2009-02-01
影响因子：
2.9
作者：
Diamond, Ivan R.;Sterescu, Anca;Wales, Paul W.
通讯作者：
Wales, Paul W.
DOI：
10.1002/hep.25500
发表时间：
2012-05
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
El Kasmi KC;Anderson AL;Devereaux MW;Fillon SA;Harris JK;Lovell MA;Finegold MJ;Sokol RJ
通讯作者：
Sokol RJ