A New Model of Interactive Effects of Alcohol and High-Fat Diet on Hepatic Fibrosis
A New Model of Interactive Effects of Alcohol and High-Fat Diet on Hepatic Fibrosis
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DOI：
10.1111/j.1530-0277.2011.01472.x
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发表时间：
2011-07-01
影响因子：
3.2
通讯作者：
Hellerbrand, Claus
中科院分区：
文献类型：
--
作者：
Gaebele, Erwin;Dostert, Karin;Hellerbrand, Claus
背景资料：酒精性脂肪性肝炎（ASH）和非酒精性脂肪性肝炎（NASH）分别是西方世界导致肝酶升高和肝硬化的最常见疾病。然而，尽管有强有力的流行病学证据表明肝损伤进展的联合作用，但病理生理机制的相互作用尚未完全了解。本研究的目的是建立和分析一种实验性小鼠模型，在该模型中，我们将慢性酒精给药与NASH诱导的高脂（HF）饮食相结合。将Balb/c小鼠随机分成4个实验组，分别接受（i）标准食物，（ii）HF饮食，（iii）饮用水中的酒精（增加浓度至5%），或（iv）HF饮食和自由饮酒6周。HF饮食显著诱导肝脏甘油三酯积累和促炎基因表达（p47（phox）和肿瘤坏死因子），而酒精单独的影响不太明显。然而，与HF饮食相结合，酒精显着增强促炎基因的表达相比，HF饮食单独。此外，酒精以及HF饮食导致促纤维化基因（I型胶原蛋白和转化生长因子-β）显著增加，肝星状细胞活化和肝组织细胞外基质沉积，值得注意的是，酒精和HF饮食的组合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，并且在接受两者的小鼠中进一步显著增加。此外，令人惊讶的是，单独的HF饮食和与酒精组合导致内毒素受体Toll样受体4（TLR 4）的肝脏表达显著增加，已知其在肝纤维化中起关键作用。总之，这种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饮食似乎协同作用于肝纤维化的发展，可能通过增强的TLR 4信号传导。
Background: 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.Methods: 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.Results: 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-beta), 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.Conclusions: 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.