Ferrebee Courtney B, Li Jianing, Haywood Jamie, Pachura Kimberly, Robinson Brian S, Hinrichs Benjamin H, Jones Rheinallt M, Rao Anuradha, Dawson Paul A
Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, Georgia.
Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
Cell Mol Gastroenterol Hepatol. 2018 Jan 12;5(4):499-522. doi: 10.1016/j.jcmgh.2018.01.006. eCollection 2018.
BACKGROUND & AIMS: Ileal bile acid absorption is mediated by uptake via the apical sodium-dependent bile acid transporter (ASBT), and export via the basolateral heteromeric organic solute transporter α-β (OSTα-OSTβ). In this study, we investigated the cytotoxic effects of enterocyte bile acid stasis in mice, including the temporal relationship between intestinal injury and initiation of the enterohepatic circulation of bile acids.
Ileal tissue morphometry, histology, markers of cell proliferation, gene, and protein expression were analyzed in male and female wild-type and mice at postnatal days 5, 10, 15, 20, and 30. mice were generated and analyzed. Bile acid activation of intestinal Nrf2-activated pathways was investigated in .
As early as day 5, mice showed significantly increased ileal weight per length, decreased villus height, and increased epithelial cell proliferation. This correlated with premature expression of the Asbt and induction of bile acid-activated farnesoid X receptor target genes in neonatal mice. Expression of reduced nicotinamide adenine dinucleotide phosphate oxidase-1 and Nrf2-anti-oxidant responsive genes were increased significantly in neonatal mice at these postnatal time points. Bile acids also activated Nrf2 in enterocytes and enterocyte-specific knockdown of Nrf2 increased sensitivity of flies to bile acid-induced toxicity. Inactivation of the Asbt prevented the changes in ileal morphology and induction of anti-oxidant response genes in mice.
Early in postnatal development, loss of Ostα leads to bile acid accumulation, oxidative stress, and a restitution response in ileum. In addition to its essential role in maintaining bile acid homeostasis, Ostα-Ostβ functions to protect the ileal epithelium against bile acid-induced injury. NCBI Gene Expression Omnibus: GSE99579.
回肠胆汁酸吸收通过顶端钠依赖性胆汁酸转运体（ASBT）摄取以及基底外侧异源有机溶质转运体α-β（OSTα-OSTβ）输出介导。在本研究中，我们调查了小鼠肠细胞胆汁酸淤积的细胞毒性作用，包括肠道损伤与胆汁酸肠肝循环启动之间的时间关系。
在出生后第5、10、15、20和30天，对雄性和雌性野生型及[缺失相关基因的]小鼠的回肠组织形态计量学、组织学、细胞增殖标志物、基因和蛋白表达进行分析。[缺失相关基因的]小鼠被构建并进行分析。在[缺失相关基因的]小鼠中研究了肠道Nrf2激活途径的胆汁酸激活情况。
早在第5天，[缺失相关基因的]小鼠就显示出回肠单位长度重量显著增加、绒毛高度降低以及上皮细胞增殖增加。这与新生[缺失相关基因的]小鼠中Asbt的过早表达以及胆汁酸激活的法尼醇X受体靶基因的诱导相关。在这些出生后时间点，新生[缺失相关基因的]小鼠中还原型烟酰胺腺嘌呤二核苷酸磷酸氧化酶-1和Nrf2抗氧化反应基因的表达显著增加。胆汁酸还激活了[缺失相关基因的]肠细胞中的Nrf2，并且肠细胞特异性敲低Nrf2增加了果蝇对胆汁酸诱导毒性的敏感性。ASBT的失活阻止了[缺失相关基因的]小鼠回肠形态的改变和抗氧化反应基因的诱导。
在出生后发育早期，Ostα的缺失导致胆汁酸积累、氧化应激以及回肠的修复反应。除了在维持胆汁酸稳态中的重要作用外，Ostα-Ostβ还起到保护回肠上皮免受胆汁酸诱导损伤的作用。NCBI基因表达综合数据库：GSE99579。
