过氧化物酶体增殖物激活受体 α 的激活可改善肝硬化大鼠的血管内皮功能障碍，并减少纤维化和门脉压。

PPARα activation improves endothelial dysfunction and reduces fibrosis and portal pressure in cirrhotic rats.

机构信息

Hepatic Hemodynamic Laboratory, Liver Unit, IMDIM, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Ciberehd, University of Barcelona, Spain.

出版信息

J Hepatol. 2012 May;56(5):1033-1039. doi: 10.1016/j.jhep.2011.12.008. Epub 2012 Jan 13.

DOI:10.1016/j.jhep.2011.12.008

PMID:22245887

Abstract

BACKGROUND & AIMS: Peroxisome proliferator-activated receptor α (PPARα) is a transcription factor activated by ligands that regulates genes related to vascular tone, oxidative stress, and fibrogenesis, pathways implicated in the development of cirrhosis and portal hypertension. This study aims at evaluating the effects of PPARα activation with fenofibrate on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl(4)-cirrhotic rats.

METHODS

Mean arterial pressure (MAP), portal pressure (PP), and portal blood flow (PBF) were measured in cirrhotic rats treated with oral fenofibrate (25mg/kg/day, n=10) or its vehicle (n=12) for 7 days. The liver was then perfused and dose-relaxation curves to acetylcholine (Ach) were performed. We also evaluated Sirius Red staining of liver sections, collagen-I mRNA expression, and smooth muscle actin (α-SMA) protein expression, cyclo-oxygenase-1 (COX-1) protein expression, and cGMP levels in liver homogenates, and TXB(2) production in perfusates. Nitric oxide (NO) bioavailability and eNOS activation were measured in hepatic endothelial cells (HEC) isolated from cirrhotic rat livers.

RESULTS

CCl(4) cirrhotic rats treated with fenofibrate had a significantly lower PP (-29%) and higher MAP than those treated with vehicle. These effects were associated with a significant reduction in hepatic fibrosis and improved vasodilatory response to acetylcholine. Moreover, a reduction in COX-1 expression and TXB(2) production in rats receiving fenofibrate and a significant increase in NO bioavailability in HEC with fenofibrate were observed.

CONCLUSIONS

PPARα activation markedly reduced PP and liver fibrosis and improved hepatic endothelial dysfunction in cirrhotic rats, suggesting it may represent a new therapeutic strategy for portal hypertension in cirrhosis.

摘要

背景与目的

过氧化物酶体增殖物激活受体α（PPARα）是一种配体激活的转录因子，可调节与血管张力、氧化应激和纤维化相关的基因，这些途径与肝硬化和门静脉高压的发展有关。本研究旨在评估用非诺贝特激活 PPARα对 CCl4 诱导的肝硬化大鼠肝和全身血液动力学、肝内皮功能障碍和肝纤维化的影响。

方法

在接受口服非诺贝特（25mg/kg/天，n=10）或其载体（n=12）治疗 7 天的肝硬化大鼠中测量平均动脉压（MAP）、门静脉压（PP）和门静脉血流量（PBF）。然后对肝脏进行灌注，并进行乙酰胆碱（Ach）剂量松弛曲线。我们还评估了肝切片的 Sirius Red 染色、胶原-I mRNA 表达和平滑肌肌动蛋白（α-SMA）蛋白表达、肝匀浆中环氧化酶-1（COX-1）蛋白表达和 cGMP 水平，以及灌注液中 TXB2 的产生。还测量了来自肝硬化大鼠肝脏的肝内皮细胞（HEC）中的一氧化氮（NO）生物利用度和 eNOS 激活。

结果

用非诺贝特治疗的 CCl4 诱导的肝硬化大鼠的 PP 显著降低（-29%），MAP 高于用载体治疗的大鼠。这些作用与肝纤维化的显著减少和乙酰胆碱引起的血管舒张反应的改善有关。此外，用非诺贝特治疗的大鼠中 COX-1 表达和 TXB2 产生减少，而用非诺贝特治疗的 HEC 中 NO 生物利用度显著增加。