叉头盒A2（HNF-3beta）转录因子的肝细胞水平升高会导致出生后脂肪变性和线粒体损伤。,Hepatology

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叉头盒A2（HNF-3beta）转录因子的肝细胞水平升高会导致出生后脂肪变性和线粒体损伤。
Hepatology ( IF 12.9 ) Pub Date : 2003-05-30 , DOI: 10.1053/jhep.2003.50253
Douglas E Hughes ₁ , Donna Beer Stolz , Songtao Yu , Yongjun Tan , Janardan K Reddy , Simon C Watkins , Anna Mae Diehl , Robert H Costa

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叉头盒（Fox）转录因子Foxa2（HNF-3beta）和相关家族成员Foxa1（HNF-3alpha）和Foxa3（HNF-3gamma）与其他肝细胞核因子（HNF）协同作用，以协调调节肝脏特异性基因表达。为了规避Foxa蛋白的肝功能冗余，我们使用了T-77转基因（TG）小鼠品系，其中-3-kb转甲状腺素蛋白（TTR）启动子起着增加Foxa2 cDNA肝细胞表达的作用。成年TG小鼠表现出降低的肝糖原和进行性肝损伤，但维持正常的血清葡萄糖，胰岛素和胰高血糖素水平。在这项研究中，我们进一步表征了TTR-FoxA2 TG小鼠的产后肝缺陷。出生后的TG小鼠显示血清葡萄糖水平和肝细胞糖原存储量显着降低，而酮体和游离脂肪酸的血清水平却未升高，这表明它们未经历饥饿反应。我们显示，TG肝脏发展出了实质性的暂时性脂肪变性，在出生后第5天达到最大值，并与参与脂肪酸和甘油三酸酯合成，脂质β-氧化和氨基酸生物合成的肝基因表达增加有关。此外，产后TG肝的透射电子显微镜分析显示广泛的线粒体膜损伤，这很可能是由于脂质β-氧化产生的活性氧。总之，我们的模型建议，针对肝细胞糖原存储量的减少，

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Elevated hepatocyte levels of the Forkhead box A2 (HNF-3beta) transcription factor cause postnatal steatosis and mitochondrial damage.

The Forkhead box (Fox) transcription factor Foxa2 (HNF-3beta) and related family members Foxa1 (HNF-3alpha) and Foxa3 (HNF-3gamma) act in concert with other hepatocyte nuclear factors (HNF) to coordinately regulate liver-specific gene expression. To circumvent the hepatic functional redundancy of the Foxa proteins, we used the T-77 transgenic (TG) mouse line in which the -3-kb transthyretin (TTR) promoter functioned to increase hepatocyte expression of the Foxa2 cDNA. Adult TG mice exhibited reduced hepatic glycogen and progressive liver injury, but maintained normal serum levels of glucose, insulin, and glucagon. In this study, we further characterized the postnatal liver defect in TTR-FoxA2 TG mice. The postnatal TG mice displayed significant reduction in serum glucose levels and in hepatocyte glycogen storage without increased serum levels of ketone bodies and free fatty acid suggesting that they are not undergoing a starvation response. We show that TG liver developed a substantial transient steatosis, which reached a maximum at postnatal day 5 and is associated with increased expression of hepatic genes involved in fatty acid and triglyceride synthesis, lipid beta-oxidation, and amino acid biosynthesis. Furthermore, transmission electron microscopy analysis of postnatal TG liver revealed extensive mitochondrial membrane damage, which is likely due to reactive oxygen species generated from lipid beta-oxidation. In conclusion, our model proposes that in response to reduction in hepatocyte glycogen storage, the TTR-Foxa2 TG mice survive by maintaining sufficient serum levels of glucose through gluconeogenesis using deaminated amino acids with dicarboxylate products of peroxisomal lipid beta-oxidation shuttled through the tricarboxylic acid cycle.

更新日期：2019-11-01

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