Farnesoid X Receptor Deficiency Induces Nonalcoholic Steatohepatitis in Low-Density Lipoprotein Receptor-Knockout Mice Fed a High-Fat Diet
Farnesoid X Receptor Deficiency Induces Nonalcoholic Steatohepatitis in Low-Density Lipoprotein Receptor-Knockout Mice Fed a High-Fat Diet
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DOI：
10.1124/jpet.108.144600
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发表时间：
2009-01-01
影响因子：
3.5
通讯作者：
Guo, Grace L.
中科院分区：
文献类型：
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作者：
Kong, Bo;Luyendyk, James P.;Guo, Grace L.
非酒精性脂肪性肝炎 (NASH) 包括脂质代谢失调和炎症。鉴定 NASH 的各种遗传和环境易感因素可能会提供限制患者炎症和纤维化的新疗法。本研究利用高胆固醇血症小鼠模型、低密度脂蛋白受体敲除 (LDLr-/-) 小鼠喂养高脂肪饮食 5 个月，来检验法尼醇 X 受体 (FXR) 缺乏导致 NASH 发展的假设。高脂肪饮食或 FXR 缺乏都会增加血清丙氨酸氨基转移酶活性，而只有 FXR 缺乏才会增加胆汁酸和碱性磷酸酶水平。 FXR 缺乏和高脂肪喂养会增加血清胆固醇和甘油三酯。尽管无论基因型如何，高脂肪都会导致小鼠肝脏中的大脂肪变性和肝细胞膨胀，但在 LDLr-/- 小鼠的肝脏中没有观察到炎症浸润。相反，在LDLr-/-/FXR-/-小鼠的肝脏中，在喂食对照饮食时偶尔观察到炎症细胞灶，而在喂食高脂肪饮食时则大大增加。与炎症细胞增强相一致，LDLr-/-/FXR-/- 小鼠的高脂饮食导致肝脏肿瘤坏死因子 α 和细胞间粘附分子 1 mRNA 水平增加。与 1 型胶原蛋白 1 α 1 和 TGF-β mRNA 水平升高相一致，喂食高脂肪饮食的 LDLr-/-/FXR-/- 小鼠肝脏中 1 型胶原蛋白水平升高。总之，FXR 缺乏会在高胆固醇血症小鼠模型中诱发 NASH 诊断所需的病理表现，包括大脂肪变性、肝细胞气球样变和炎症，这表明 FXR 缺乏和高脂肪饮食的结合是 NASH 发生的危险因素，而 FXR 的激活可能是治疗 NASH 的一种治疗干预措施。
Nonalcoholic steatohepatitis (NASH) comprises dysregulation of lipid metabolism and inflammation. Identification of the various genetic and environmental susceptibility factors for NASH may provide novel treatments to limit inflammation and fibrosis in patients. This study utilized a mouse model of hypercholesterolemia, low-density lipoprotein receptor knockout (LDLr-/-) mice fed a high-fat diet for 5 months, to test the hypothesis that farnesoid X receptor (FXR) deficiency contributed to NASH development. Either the high-fat diet or FXR deficiency increased serum alanine aminotransferase activity, whereas only FXR deficiency increased bile acid and alkaline phosphatase levels. FXR deficiency and high-fat feeding increased serum cholesterol and triglycerides. Although high fat led to macrosteatosis and hepatocyte ballooning in livers of mice regardless of genotype, no inflammatory infiltrate was observed in the livers of LDLr-/- mice. In contrast, in the livers of LDLr-/-/FXR-/- mice, foci of inflammatory cells were observed occasionally when fed the control diet and were greatly increased when fed the high-fat diet. Consistent with enhanced inflammatory cells, hepatic levels of tumor necrosis factor alpha and intercellular adhesion molecule-1 mRNA were increased by the high-fat diet in LDLr-/-/FXR-/- mice. In agreement with elevated levels of procollagen 1 alpha 1 and TGF-beta mRNA, type 1 collagen protein levels were increased in livers of LDLr-/-/FXR-/- mice fed a high-fat diet. In conclusion, FXR deficiency induces pathologic manifestations required for NASH diagnosis in a mouse model of hypercholesterolemia, including macrosteatosis, hepatocyte ballooning, and inflammation, which suggest a combination of FXR deficiency and high-fat diet is a risk factor for NASH development, and activation of FXR may be a therapeutic intervention in the treatment of NASH.