Department of Internal Medicine I, University Medical Centre Regensburg, Regensburg, Germany.
Alcohol Clin Exp Res. 2011 Jul;35(7):1361-7. doi: 10.1111/j.1530-0277.2011.01472.x. Epub 2011 Apr 4.
Alcoholic steatohepatitis (ASH) and nonalcoholic steatohepatitis (NASH) are the most frequent conditions leading to elevated liver enzymes and liver cirrhosis, respectively, in the Western world. However, despite strong epidemiological evidence for combined effects on the progression of liver injury, the mutual interaction of the pathophysiological mechanisms is incompletely understood. The aim of this study was to establish and analyze an experimental murine model, where we combined chronic alcohol administration with a NASH-inducing high-fat (HF) diet.
Balb/c mice were randomly allocated into 4 experimental groups receiving (i) standard chow, (ii) an HF diet, (iii) alcohol in drinking water (increasing concentrations up to 5%), or (iv) an HF diet and alcohol ad libitum for 6 weeks.
An HF diet significantly induced hepatic triglyceride accumulation and expression of proinflammatory genes (p47(phox) and tumor necrosis factor), while the effects of alcohol alone were less pronounced. However, in combination with HF diet, alcohol significantly enhanced proinflammatory gene expression compared to the HF diet alone. Furthermore, alcohol as well as HF diet led to a marked increase in profibrogenic genes (collagen type I and transforming growth factor-β), activation of hepatic stellate cells, and extracellular matrix deposition in the liver tissue, and noteworthy, the combination of both alcohol and HF diet led to a further marked induction of hepatic fibrosis. Moreover, endotoxin levels in the portal circulation were significantly elevated in mice that received alcohol or HF diet and were further significantly increased in those receiving both. Furthermore and surprisingly, HF diet alone and in combination with alcohol led to a markedly increased hepatic expression of the endotoxin receptor Toll-like receptor 4 (TLR4), which is known to play a crucial role in hepatic fibrosis.
In summary, this new model allows the investigation of isolated or joint effects of alcohol and HF diet on hepatic injury, where alcohol and HF diet appear to act synergistically on the development of hepatic fibrosis, potentially via enhanced TLR4 signaling.
在西方国家，酒精性脂肪性肝炎（ASH）和非酒精性脂肪性肝炎（NASH）分别是导致肝酶升高和肝硬化的最常见疾病。然而，尽管有强烈的流行病学证据表明两者对肝损伤的进展有共同作用，但病理生理机制的相互作用仍不完全清楚。本研究旨在建立和分析一种实验性的小鼠模型，在该模型中我们将慢性酒精摄入与 NASH 诱导的高脂肪（HF）饮食相结合。
Balb/c 小鼠被随机分配到 4 个实验组，分别接受（i）标准饲料、（ii）HF 饮食、（iii）饮用水中的酒精（浓度逐渐增加至 5%）或（iv）HF 饮食和酒精自由摄取，共 6 周。
HF 饮食显著诱导肝内甘油三酯蓄积和促炎基因（p47(phox)和肿瘤坏死因子）的表达，而单独使用酒精的作用则不那么明显。然而，与 HF 饮食联合使用时，酒精显著增强了促炎基因的表达，与 HF 饮食单独使用相比。此外，酒精和 HF 饮食均导致显著增加促纤维化基因（I 型胶原和转化生长因子-β）、肝星状细胞的激活和肝组织中细胞外基质的沉积，值得注意的是，两者联合使用导致肝纤维化的进一步显著诱导。此外，接受酒精或 HF 饮食的小鼠门静脉循环中的内毒素水平显著升高，而接受两者联合使用的小鼠内毒素水平进一步显著升高。此外，令人惊讶的是，HF 饮食单独和联合使用酒精导致肝内内毒素受体 Toll 样受体 4（TLR4）的表达显著增加，TLR4 已知在肝纤维化中起关键作用。
总之，这个新模型允许研究酒精和 HF 饮食对肝损伤的单独或联合作用，其中酒精和 HF 饮食似乎在肝纤维化的发展中具有协同作用，可能通过增强 TLR4 信号传导。
