Section of Pediatric Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, United States.
The Digestive Health Institute, University of Colorado School of Medicine, Aurora, Colorado, United States.
Am J Physiol Gastrointest Liver Physiol. 2024 Dec 1;327(6):G754-G764. doi: 10.1152/ajpgi.00042.2024. Epub 2024 Sep 20.
We have developed a mouse model of parenteral nutrition-associated liver disease (PNALD) in which parenteral nutrition (PN) infusion results in cholestatic liver injury. In the liver, the master circadian genes /Bmal drive rhythmic gene expression and regulate circadian expression of hepatic functions including bile acid synthesis. The aim of this study was to examine the effect of continuous PN on ileal and hepatic expression of circadian regulatory (CR) genes, farnesoid X receptor (FXR) signaling, and bile acid synthesis in mice. Wild-type mice were exposed to ad libitum Chow or continuous soy oil lipid emulsion-based PN infusion through a central venous catheter for 4 days (PN). Water was provided ad libitum, but no nutrients were provided enterally. On , separate groups of Chow and PN-fed mice were euthanized every 6 h (7 AM, 1 PM, 7 PM, and 1 AM), and ileal, hepatic tissue and serum harvested. From tissue samples, the relative expression of circadian transcription factors and FXR signaling was assessed. Administration of 4-day PN increased hepatic injury, inflammatory cytokine expression, and gut permeability. In the ileum, PN activated FXR and induced expression of and . In the liver, expression of FXR-downstream targets was dysregulated. PN administrations impacted hepatic and ileal circadian transcription factor mRNA expression, which was discordant between the two organs. Dysregulation of circadian regulatory machinery is in part due to discordance of the gut-liver axis during PN. Pharmacological targeting of CR as a therapeutic strategy for PNALD thus deserves further investigation. This study used a novel short-term model of parenteral nutrition (PN) that is translationally relevant. We find that short-term PN is sufficient to induce hepatic and ileal changes in circadian transcription factor expression and to prevent normal concordant coordination of circadian transcription factors between the ileum and liver. These data suggest that targeting circadian transcription may have some clinical benefit in patients receiving parenteral nutrition.
我们构建了一种肠外营养相关性肝病（PNALD）的小鼠模型，该模型通过肠外营养（PN）输注导致胆汁淤积性肝损伤。在肝脏中，主生物钟基因 /Bmal 驱动节律性基因表达，并调节包括胆汁酸合成在内的肝脏功能的昼夜节律表达。本研究旨在研究连续 PN 对小鼠回肠和肝脏中昼夜节律调节（CR）基因、法尼醇 X 受体（FXR）信号和胆汁酸合成的影响。野生型小鼠接受自由进食对照饲料或通过中心静脉导管进行连续大豆油脂肪乳剂 PN 输注 4 天（PN）。自由饮水，但不提供肠内营养。在第 4 天，将分别给予对照饲料和 PN 喂养的小鼠每 6 小时处死一组（7 AM、1 PM、7 PM 和 1 AM），并采集回肠、肝脏组织和血清。从组织样本中评估昼夜节律转录因子和 FXR 信号的相对表达。给予 4 天 PN 会增加肝损伤、炎症细胞因子表达和肠道通透性。在回肠中，PN 激活了 FXR 并诱导了 和 的表达。在肝脏中，FXR 下游靶标的表达失调。PN 给药会影响肝脏和回肠昼夜节律转录因子 mRNA 的表达，这在两个器官之间存在差异。昼夜节律调节机制的失调部分是由于 PN 期间肠道-肝脏轴的不协调。因此，作为 PNALD 的治疗策略，针对 CR 的药理学靶向值得进一步研究。本研究使用了一种新颖的短期肠外营养（PN）模型，具有转化相关性。我们发现，短期 PN 足以诱导肝脏和回肠中昼夜节律转录因子表达的变化，并防止回肠和肝脏之间昼夜节律转录因子的正常协调。这些数据表明，针对昼夜节律转录因子可能对接受肠外营养的患者具有一定的临床益处。
