Increased susceptibility to exacerbated liver injury in hypercholesterolemic ApoE-deficient mice: potential involvement of oxysterols
Increased susceptibility to exacerbated liver injury in hypercholesterolemic ApoE-deficient mice: potential involvement of oxysterols
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DOI：
10.1152/ajpgi.00547.2007
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发表时间：
2009-03-01
影响因子：
4.5
通讯作者：
Claria, Joan
中科院分区：
文献类型：
--
作者：
Ferre, Natalia;Martinez-Clemente, Marcos;Claria, Joan
Ferre N，Martinez-Clemente M，Lopez-Parra M，Gonzalez-Periz A，Horrillo R，Planaguma A，Camps J，Joven J，Tres A，Guardiola F，Bataller R，Arroyo V，Claria J。高胆固醇血症 ApoE 缺陷小鼠对加重肝损伤的易感性增加：氧甾醇的潜在参与。 Am J Physiol Gastrointest Liver Physiol 296：G553-G562，2009。首次发表于 2009 年 1 月 8 日； doi:10.1152/ajpgi.00547.2007.-代谢因素对肝病严重程度的影响尚不完全清楚。在这项研究中，对载脂蛋白 E 缺陷 (ApoE(-/-)) 小鼠进行了评估，以确定高胆固醇血症对四氯化碳 (CCl4) 诱导的肝损伤严重程度的潜在影响。在基线条件下，高胆固醇血症 ApoE(-/-) 小鼠表现出比野生型对照小鼠更高的肝脏氧化应激（SOD 活性/4-羟基-2-壬烯醛免疫染色）和更高的肝脏 TGF-β 1、MCP-1 和 TIMP-1 表达。 CCl4攻击后，ApoE(-/-)小鼠表现出加剧的脂肪变性（油红O染色）、坏死性炎症（苏木精-伊红染色）、巨噬细胞浸润（F4/80免疫组织化学）和纤维化（天狼星红染色和α-平滑肌肌动蛋白免疫组织化学）和更严重的肝损伤[丙氨酸转氨酶（ALT）和天冬氨酸转氨酶]比野生型对照。血清胆固醇与肝脏脂肪变性、纤维化和 ALT 水平之间存在直接相关性。这些变化并不反映 ApoE(-/-) 小鼠疾病的通常进展，因为在未经治疗的年龄配对 ApoE(-/-) 小鼠中不存在加重的肝损伤。此外，ApoE(-/-)小鼠的肝细胞色素P-450表达没有变化。为了探索潜在的机制，将与肝脏病理生理学相关的细胞类型暴露于选定的胆固醇氧化产物。将肝细胞与代表GC-MS在ApoE(-/-)小鼠肝脏中检测到的氧甾醇混合物一起孵育，导致总脂过氧化物和SOD活性呈浓度依赖性增加。在肝星状细胞中，氧甾醇通过不依赖 NF-κ B 的机制增加 IL-8 的分泌，并上调 TIMP-1 的表达。在巨噬细胞中，氧甾醇以浓度依赖性方式增加 TGF-β1 分泌和 MCP-1 表达。氧甾醇不会损害细胞活力。总而言之，这些发现表明，高胆固醇血症小鼠对肝损伤敏感，并且胆固醇衍生产品（即氧甾醇）能够诱导肝细胞中的促炎和促纤维形成机制。
Ferre N, Martinez-Clemente M, Lopez-Parra M, Gonzalez-Periz A, Horrillo R, Planaguma A, Camps J, Joven J, Tres A, Guardiola F, Bataller R, Arroyo V, Claria J. Increased susceptibility to exacerbated liver injury in hypercholesterolemic ApoE-deficient mice: potential involvement of oxysterols. Am J Physiol Gastrointest Liver Physiol 296: G553-G562, 2009. First published January 8, 2009; doi:10.1152/ajpgi.00547.2007.-The contribution of metabolic factors to the severity of liver disease is not completely understood. In this study, apolipoprotein E-deficient (ApoE(-/-)) mice were evaluated to define potential effects of hypercholesterolemia on the severity of carbon tetrachloride (CCl4)-induced liver injury. Under baseline conditions, hypercholesterolemic ApoE(-/-) mice showed increased hepatic oxidative stress (SOD activity/4-hydroxy-2-nonenal immunostaining) and higher hepatic TGF-beta 1, MCP-1, and TIMP-1 expression than wild-type control mice. After CCl4 challenge, ApoE(-/-) mice exhibited exacerbated steatosis (Oil Red O staining), necroinflammation (hematoxylin-eosin staining), macrophage infiltration (F4/80 immunohistochemistry), and fibrosis (Sirius red staining and alpha-smooth muscle actin immunohistochemistry) and more severe liver injury [alanine aminotransferase (ALT) and aspartate aminotransferase] than wild-type controls. Direct correlations were identified between serum cholesterol and hepatic steatosis, fibrosis, and ALT levels. These changes did not reflect the usual progression of the disease in ApoE(-/-) mice, since exacerbated liver injury was not present in untreated age-paired ApoE(-/-) mice. Moreover, hepatic cytochrome P-450 expression was unchanged in ApoE(-/-) mice. To explore potential mechanisms, cell types relevant to liver pathophysiology were exposed to selected cholesterol-oxidized products. Incubation of hepatocytes with a mixture of oxysterols representative of those detected by GC-MS in livers from ApoE(-/-) mice resulted in a concentration-dependent increase in total lipoperoxides and SOD activity. In hepatic stellate cells, oxysterols increased IL-8 secretion through a NF-kappa B-independent mechanism and upregulated TIMP-1 expression. In macrophages, oxysterols increased TGF-beta 1 secretion and MCP-1 expression in a concentration-dependent manner. Oxysterols did not compromise cell viability. Taken together, these findings demonstrate that hypercholesterolemic mice are sensitized to liver injury and that cholesterol-derived products (i.e., oxysterols) are able to induce proinflammatory and profibrogenic mechanisms in liver cells.