Liver-Specific β-Catenin Knockout Mice Exhibit Defective Bile Acid and Cholesterol Homeostasis and Increased Susceptibility to Diet-Induced Steatohepatitis
Liver-Specific β-Catenin Knockout Mice Exhibit Defective Bile Acid and Cholesterol Homeostasis and Increased Susceptibility to Diet-Induced Steatohepatitis
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DOI：
10.2353/ajpath.2010.090667
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发表时间：
2010-02-01
影响因子：
6
通讯作者：
Monga, Satdarshan P. S.
中科院分区：
文献类型：
--
作者：
Behari, Jaideep;Yeh, Tzu-Hsuan;Monga, Satdarshan P. S.
尽管Wnt/β-catenin信号在肝脏生长发育中的作用已被证实，但其在非肿瘤性肝脏病理中的作用尚未被研究。在这里，我们研究了β-连环蛋白在饮食诱导的小鼠肝损伤模型中的作用。肝细胞特异性β-连环蛋白缺失(KO)小鼠和白蚁对照小鼠被饲喂脂肪生成蛋氨酸和胆碱缺乏(MCD)饲料或相应的对照饲料2周，并对其组织学、生化和分子变化进行表征。与野生型小鼠相比，食用MCD饮食的KO小鼠发生了显著更高的脂肪性肝炎和纤维化。野生型和KO肝脏在MCD饮食中都积累了甘油三酯，但出乎意料的是，在对照组和MCD饮食中，KO肝脏中观察到了更高的肝脏胆固醇水平。基因表达分析表明，肝脏胆固醇在KO肝脏中的积累不是由于合成或摄取增加所致。KO小鼠胆汁酸合成酶表达较低，但肝脏胆汁酸和血清胆红素水平较高，提示胆汁输出存在缺陷。因此，肝脏中β-连环蛋白的丢失会导致肝脏中胆固醇和胆汁酸代谢的缺陷，并增加在代谢应激下发生脂肪性肝炎的易感性。(Am J Pathol2010,176：744-753；DOI：10.2353/ajpath.2010.090667)
Although the role of Wnt/beta-catenin signaling in liver growth and development is well established, its contribution in non-neoplastic hepatic pathologies has not been investigated. Here, we examine the role of beta-catenin in a murine model of diet-induced liver injury. Mice with hepatocyte-specific beta-catenin deletion (KO) and tittermate controls were fed the steatogenic methionine and choline-deficient (MCD) diet or the corresponding control diet for 2 weeks and characterized for histological, biochemical, and molecular changes. KO mice developed significantly higher steatohepatitis and fibrosis on the MCD diet compared with wild-type mice. Both wild-type and KO livers accumulated triglyceride on the MCD diet but, unexpectedly, higher hepatic cholesterol levels were observed in KO livers on both control and MCD diets. Gene expression analysis showed that hepatic cholesterol accumulation in KO livers was not attributable to increased synthesis or uptake. KO mice had lower expression of bile acid synthetic enzymes but exhibited higher hepatic bile acid and serum bilirubin levels, suggesting defects in bile export. Therefore, loss of beta-catenin in the liver leads to defective cholesterol and bile acid metabolism in the liver and increased susceptibility to developing steatohepatitis in the face of metabolic stress. (Am J Pathol 2010, 176:744-753; DOI: 10.2353/ajpath.2010.090667)