Accumulation of free cholesterol and oxidized low-density lipoprotein is associated with portal inflammation and fibrosis in nonalcoholic fatty liver disease
Accumulation of free cholesterol and oxidized low-density lipoprotein is associated with portal inflammation and fibrosis in nonalcoholic fatty liver disease
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DOI：
10.1186/s12950-019-0211-5
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发表时间：
2019-04-02
影响因子：
5.1
通讯作者：
Lee, Po-Huang
中科院分区：
文献类型：
--
作者：
Ho, Cheng-Maw;Ho, Shu-Li;Lee, Po-Huang
背景巨噬细胞吞噬氧化低密度脂蛋白（oxLDL），导致细胞胆固醇蓄积和泡沫细胞形成，是动脉粥样硬化的标志。此外，最近的研究表明，巨噬细胞中游离胆固醇的积累导致NLRP 3炎性体的活化和白细胞介素-1（IL-1）的产生与动脉粥样硬化相关的炎症有关。然而，目前尚不清楚胆固醇蓄积是否与肝脏炎症和肝纤维化有关。在这项研究中，我们研究了门静脉游离胆固醇和oxLDL积聚与人类非酒精性脂肪性肝病（NAFLD）的炎症，动脉粥样硬化和纤维化的关系。oxLDL和凝集素样oxLDL受体-1（LOX-1）。结果门静脉壁oxLDL和游离胆固醇共存，并与门静脉管腔狭窄、斑块形成、内皮变形和门静脉炎症有关。枯否细胞和IL-1的共定位以及LOX-1的表达证实了炎症。值得注意的是，破裂斑块与门静脉炎症密切相关。此外，游离胆固醇和oxLDL积累在门静脉周围和窦状隙纤维化，这是与区域星状细胞活化和chicken-wire fibrosis.ConclusionThese研究结果揭示了胆固醇积累，门静脉炎症和纤维化之间的直接关联在NAFLD。
BackgroundMacrophages engulf oxidized-LDL (oxLDL) leading to accumulation of cellular cholesterol and formation of foam cells, which is a hallmark of atherosclerosis. Moreover, recent studies showed that accumulation of free cholesterol in macrophages leading to activation of NLRP3 inflammasome and production of interleukin-1 (IL-1) has been linked to atherosclerosis-associated inflammation. However, it is not clear if cholesterol accumulation is associated with hepatic inflammation and fibrosis in the liver. In this study, we investigated the association of free cholesterol and oxLDL accumulation in portal vein with the inflammation, atherosclerosis, and fibrosis in human nonalcoholic fatty liver disease (NAFLD).MethodsSerial sections derived from surgical specimens of NAFLD were stained with filipin and antibodies against IL-1, CD68, -smooth muscle actin (-SMA), oxLDL and lectin-like oxLDL receptor-1 (LOX-1).ResultsWe show that free cholesterol was colocalized with oxLDL in the wall of portal vein, and which was associated with lumen narrowing, plaque formation, endothelium deformation, and portal venous inflammation. The inflammation was evidenced by the colocalization of Kupffer cells and IL-1 and the expression of LOX-1. Notably, ruptured plaque was closely associated with portal venous inflammation. Moreover, free cholesterol and oxLDL accumulation in periportal and sinusoidal fibrosis, which was associated with regional stellate cell activation and chicken-wire fibrosis.ConclusionThese findings reveal a direct association between cholesterol accumulation, portal venous inflammation and fibrosis in NAFLD.