Dysregulation of Kupffer Cells/Macrophages and Natural Killer T Cells in Steatohepatitis in LXRα Knockout Male Mice
Dysregulation of Kupffer Cells/Macrophages and Natural Killer T Cells in Steatohepatitis in LXRα Knockout Male Mice
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DOI：
10.1210/en.2017-03141
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发表时间：
2018-03-01
期刊：
影响因子：
4.8
通讯作者：
Makishima, Makoto
中科院分区：
文献类型：
--
作者：
Endo-Umeda, Kaori;Nakashima, Hiroyuki;Makishima, Makoto
肝脏X受体（LXR）α表达主要定位于代谢组织，如肝脏，而LXR β则普遍表达。LXR α被氧化固醇激活，在代谢组织中的脂质代谢调节中发挥重要作用。在巨噬细胞中，LXR刺激胆固醇反向转运并调节免疫反应。尽管高胆固醇饮食在LXR α基因敲除（KO）小鼠中诱导了严重的脂肪性肝炎，但将脂质代谢和免疫反应联系起来的潜在机制在很大程度上仍然未知。在这项研究中，我们通过评估高脂肪和高胆固醇饮食（HFCD）对野生型（WT）和LXR α-KO小鼠肝脏免疫细胞比例和功能以及脂质代谢的影响，研究了LXR α在脂肪性肝炎发病机制中的作用。与WT小鼠相比，HFCD喂养在LXR α-KO小鼠中诱导了重度脂肪性肝炎。这些小鼠在血浆和肝脏中具有较高的胆固醇水平，并且在整个肝脏样品和分离的肝脏单核细胞中LXR靶基因和促炎基因的表达失调。流式细胞术显示，在HFCD喂养的LXR α-KO小鼠的肝脏中，CD 68（+）CD 11b（+）Kupffer细胞/巨噬细胞增加，不变的自然杀伤T细胞减少。这些小鼠对脂多糖诱导的肝损伤更敏感，并且对α-半乳糖神经酰胺或伴刀豆球蛋白A治疗的炎症反应具有抗性。这些发现为骨髓源性库普弗细胞/巨噬细胞的激活和LXR α-KO小鼠肝脏中不变的自然杀伤T细胞的功能障碍提供了证据。这些发现表明，LXR α调节肝脏免疫功能沿着脂质代谢，并防止非酒精性脂肪性肝炎的发病机制。
Liver X receptor (LXR) alpha expression is mainly localized to metabolic tissues, such as the liver, whereas LXR beta is ubiquitously expressed. LXR alpha is activated by oxysterols and plays an important role in the regulation of lipid metabolism in metabolic tissues. In macrophages, LXRs stimulate reverse cholesterol transport and regulate immune responses. Although a high-cholesterol diet induces severe steatohepatitis in LXR alpha-knockout (KO) mice, the underlying mechanisms linking lipid metabolism and immune responses remain largely unknown. In this study, we investigated the role of LXR alpha in the pathogenesis of steatohepatitis by assessing the effects of a high-fat and high-cholesterol diet (HFCD) on hepatic immune cell proportion and function as well as lipid metabolism in wild-type (WT) and LXR alpha-KO mice. HFCD feeding induced severe steatohepatitis in LXR alpha-KO mice compared with WT mice. These mice had higher cholesterol levels in the plasma and the liver and dysregulated expression of LXR target and proinflammatory genes in both whole liver samples and isolated hepatic mononuclear cells. Flow cytometry showed an increase in CD68(+)CD11b(+) Kupffer cells/macrophages and a decrease in invariant natural killer T cells in the liver of HFCD-fed LXR alpha-KO mice. These mice were more susceptible to lipopolysaccharide-induced liver injury and resistant to inflammatory responses against alpha-galactosylceramide or concanavalin-A treatment. The findings provide evidence for activation of bone marrow-derived Kupffer cells/macrophages and dysfunction of invariant natural killer T cells in LXR alpha-KOmouse liver. These findings indicate that LXRa regulates hepatic immune function along with lipid metabolism and protects against the pathogenesis of nonalcoholic steatohepatitis.