Apical sodium-dependent bile acid transporter upregulation is associated with necrotizing enterocolitis

作者：Halpern Melissa D^*; Weitkamp Joern Hendrik; Patrick Sarah K Mount; Dobrenen Holly J; Khailova Ludmila; Correa Hernan; Dvorak Bohuslav

来源：American Journal of Physiology - Gastrointestinal and Liver Physiology, 2010, 299(3): G623-G631.

DOI：10.1152/ajpgi.00242.2010

• epithelial transport
• SC-435
• bile salt export pump

Halpern MD, Weitkamp J, Mount Patrick SK, Dobrenen HJ, Khailova L, Correa H, Dvorak B. Apical sodium-dependent bile acid transporter upregulation is associated with necrotizing enterocolitis. Am J Physiol Gastrointest Liver Physiol 299: G623-G631, 2010. First published July 8, 2010; doi: 10.1152/ajpgi.00242.2010.-Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency of premature infants. Previously, we showed that luminal bile acids (BAs) are increased and correlated with disease development and that the apical sodium-dependent BA transporter (ASBT), which transports BAs from the ileal lumen into enterocytes, is upregulated in rats with NEC. We hypothesized that intraenterocyte, rather than luminal, BAs are associated with NEC and that upregulation of ASBT may be a mechanism by which this occurs. Neonatal rats with or without the ASBT inhibitor SC-435, mice in which ASBT was knocked out, and mice that overproduce BAs were subjected to the NEC protocol. Disease development, ASBT, and the farnesoid X receptor protein, along with luminal and intraenterocyte BA levels, were assessed. In addition, ileal sections from premature infants with and without NEC were examined for ASBT via immunohistology and real-time PCR. When BAs were not transported into enterocytes (rats given SC-435 and ASBT knockout mice), severity and incidence of NEC were reduced. In contrast, in mice that overproduce BAs, ASBT was elevated, intraenterocyte BAs were increased, and disease development was increased. ASBT staining was more intense on the apical membrane of ileal enterocytes from premature infants with NEC than premature infants with non-NEC diagnoses. In addition, ASBT mRNA levels were significantly higher in infants with NEC. These data show that accumulation of intraenterocyte BAs contributes to disease development, elevated ASBT increases disease severity in experimental models of NEC, and ASBT is elevated in human NEC. These data confirm that BAs and upregulation of ASBT play a crucial role in NEC pathogenesis and suggest that inhibition of ASBT could be utilized as a therapeutic modality against this disease.

• 出版日期2010-9