Ibañez Patricio, Solis Nancy, Pizarro Margarita, Aguayo Gloria, Duarte Ignacio, Miquel Juan Francisco, Accatino Luigi, Arrese Marco
Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
J Gastroenterol Hepatol. 2007 Jun;22(6):846-51. doi: 10.1111/j.1440-1746.2006.04700.x.
Nonalcoholic steatohepatitis (NASH) is a metabolic disorder of the liver that may evolve into fibrosis or cirrhosis. Recent studies have shown reduction of experimental liver fibrosis with the use of angiotensin-converting-enzyme inhibitors or angiotensin-receptor antagonists. The aim of this study was to determine whether losartan can influence the early phase of fibrogenesis in an animal model of NASH.
To induce NASH, a choline-deficient diet (CDD) was given to Sprague-Dawley rats for 12 weeks. These animals were then compared with a control group receiving choline-supplemented diet (CSD) and a group fed a CDD plus losartan (10 mg/kg/day). Biochemical (serum levels of alanine aminotransferase and aspartate aminotransferase) and histological evaluation of fatty liver was performed by conventional techniques. Hydroxyproline content in liver tissue was assayed by spectrophotometry. In addition, mRNA levels of procollagen I and transforming growth factor (TGF)-beta were assessed by semiquantitative RT-PCR and stellate cell activation by alpha-actin immunofluorescence stain.
After 12 weeks CDD induced a marked elevation of serum aminotranferases, a severe fatty liver infiltration with mild histological inflammation and fibrosis. These findings correlated with a significant increase in mRNA levels of both procollagen I and TGF-beta and significant increased liver hydroxyproline content. No differences were seen between rats receiving CDD alone and rats receiving CDD plus losartan with regard to the biochemical, morphological or molecular alterations induced by the CDD.
Losartan does not seem to influence liver injury and fibrogenic events in the CDD model of NASH.
非酒精性脂肪性肝炎（NASH）是一种肝脏代谢紊乱疾病，可能会发展为肝纤维化或肝硬化。最近的研究表明，使用血管紧张素转换酶抑制剂或血管紧张素受体拮抗剂可减轻实验性肝纤维化。本研究的目的是确定氯沙坦是否能影响NASH动物模型中纤维化形成的早期阶段。
为诱导NASH，给Sprague-Dawley大鼠喂食胆碱缺乏饮食（CDD）12周。然后将这些动物与接受胆碱补充饮食（CSD）的对照组以及喂食CDD加氯沙坦（10毫克/千克/天）的组进行比较。通过常规技术进行生化检测（血清丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平）以及脂肪肝的组织学评估。通过分光光度法测定肝组织中的羟脯氨酸含量。此外，通过半定量逆转录聚合酶链反应评估I型前胶原和转化生长因子（TGF）-β的mRNA水平，并通过α-肌动蛋白免疫荧光染色评估星状细胞活化情况。
12周后，CDD导致血清氨基转移酶显著升高，严重的脂肪肝浸润伴有轻度组织学炎症和纤维化。这些发现与I型前胶原和TGF-β的mRNA水平显著增加以及肝脏羟脯氨酸含量显著增加相关。在由CDD诱导的生化、形态或分子改变方面，单独接受CDD的大鼠与接受CDD加氯沙坦的大鼠之间未观察到差异。
在NASH的CDD模型中，氯沙坦似乎不会影响肝损伤和纤维化事件。
