LKB1 is required for hepatic bile acid transport and canalicular membrane integrity in mice.
LKB1 is required for hepatic bile acid transport and canalicular membrane integrity in mice.
复制标题
DOI：
10.1042/bj20101721
复制
发表时间：
2011-02-15
期刊：
影响因子：
--
通讯作者：
Carling D
中科院分区：
文献类型：
--
作者：
Woods A;Heslegrave AJ;Muckett PJ;Levene AP;Clements M;Mobberley M;Ryder TA;Abu-Hayyeh S;Williamson C;Goldin RD;Ashworth A;Withers DJ;Carling D
LKB 1是一种"主"蛋白激酶，参与代谢、细胞增殖、细胞极性和肿瘤发生的调节。然而，LKB 1在肝功能中的长期作用尚不清楚。在本研究中，它表明，肝脏LKB 1在肝脏细胞结构和代谢中起着关键作用。我们报告，肝脏特异性LKB 1缺失小鼠导致有缺陷的小管和胆管形成，导致受损的胆汁酸清除和随后的胆汁酸在血清和肝脏中的积累。与此同时，发现大部分BSEP（胆盐输出泵）保留在细胞内池中，而不是定位于LLKB1KO（肝脏特异性Lkb1敲除）小鼠肝细胞中的小管膜。总之，这些变化导致胆盐的毒性积累，肝功能下降和无法茁壮成长。此外，循环LDL（低密度脂蛋白）-胆固醇和非酯化胆固醇水平在LLKB1KO小鼠中增加，并伴有红细胞形态学的相关改变和高胆红素血症的发生。这些结果表明，LKB 1在胆汁酸体内平衡中起关键作用，并且肝脏中LKB 1的缺乏导致胆汁淤积。这些发现表明LKB 1在肝脏形态学的发展和小管蛋白的膜靶向中具有新的关键作用。
LKB1 is a ‘master’ protein kinase implicated in the regulation of metabolism, cell proliferation, cell polarity and tumorigenesis. However, the long-term role of LKB1 in hepatic function is unknown. In the present study, it is shown that hepatic LKB1 plays a key role in liver cellular architecture and metabolism. We report that liver-specific deletion of LKB1 in mice leads to defective canaliculi and bile duct formation, causing impaired bile acid clearance and subsequent accumulation of bile acids in serum and liver. Concomitant with this, it was found that the majority of BSEP (bile salt export pump) was retained in intracellular pools rather than localized to the canalicular membrane in hepatocytes from LLKB1KO (liver-specific Lkb1-knockout) mice. Together, these changes resulted in toxic accumulation of bile salts, reduced liver function and failure to thrive. Additionally, circulating LDL (low-density lipoprotein)-cholesterol and non-esterified cholesterol levels were increased in LLKB1KO mice with an associated alteration in red blood cell morphology and development of hyperbilirubinaemia. These results indicate that LKB1 plays a critical role in bile acid homoeostasis and that lack of LKB1 in the liver results in cholestasis. These findings indicate a novel key role for LKB1 in the development of hepatic morphology and membrane targeting of canalicular proteins.