期刊
HEPATOLOGY
卷 44, 期 3, 页码 550-560出版社
WILEY
DOI: 10.1002/hep.21284
关键词
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资金
- Intramural NIH HHS Funding Source: Medline
- NCI NIH HHS [Z01 BC005708-14] Funding Source: Medline
Vascular endothelial cells (ECs) play a critical role in angiogenesis and organogenesis, especially in embryonic liver development. Hypoxia-inducible transcription factors (Hifs) are a key trigger of hypoxic signals, a primary stimulus of angiogenesis. The aryl hydrocarbon receptor nuclear translocator (Arnt), also called Hif-1 beta, serves as an obligate heterodimerization partner of Hif-1 alpha and Hif-2 alpha. Using Cre-Lox technology, the mouse Arnt gene was specifically disrupted in endothelial cells. The resulting mice, designated Arnt(Delta EC), developed impaired hepatic vasculature, liver necrosis, and degenerative lesions in cardiac myocytes at the late embryonic stage (E16.5-E18.5), leading to approximately 90% neonatal lethality. Low serum glucose, downregulation of glucose transporter-1 and glucose-6-phosphatase mRNA, and hepatocyte proliferation were observed in Arnt(Delta EC) embryos. Magnetic resonance imaging on E16.5 embryonic livers revealed that Arnt(Delta EC) mice had a significant volume of avascular region. Arnt(Delta EC) mice that survived to the adult stage were fertile, showed normal behavioral activity, but had smaller livers with mild portal fibrosis, dilated blood vessels, abnormal collagen accumulation, and remarkable iron deposition. Arnt(Delta EC) mice had reduced adiposity, impaired serum lipid homeostasis, and a higher respiratory exchange ratio, indicating they utilized relatively more carbohydrates than their Arnt(F/F) counterparts. In conclusion, endothelial Arnt plays a pivotal role in embryonic liver development. Adult Arnt(Delta EC) mice carrying embryonic hepatic defects developed what was possibly an early stage of cirrhosis with consequences of limited oxygen availability and altered lipid metabolism.
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