A high-fat diet impairs liver regeneration in C57BL/6 mice through overexpression of the NF-κB inhibitor, IκBα
A high-fat diet impairs liver regeneration in C57BL/6 mice through overexpression of the NF-κB inhibitor, IκBα
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DOI：
10.1002/hep.20879
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发表时间：
2005-11-01
期刊：
影响因子：
13.5
通讯作者：
Lambris, JD
中科院分区：
文献类型：
--
作者：
DeAngelis, RA;Markiewski, MM;Lambris, JD
尽管肥胖症的发病率越来越高，但关于这种情况以及相关的脂肪变性如何影响肝脏再生的知识仍然很少。以前的许多研究都使用了由基因改变引起的脂肪性肝炎或肥胖的模型。相比之下，我们对肝脏再生的研究主要集中在肥胖的影响上，这完全是由于饮食中的高脂肪造成的。这一模型更贴切地反映了饮食习惯的有害影响，饮食习惯是导致西方发达社会肥胖及其并发症发病率增加的原因。在喂食高脂饮食的小鼠中，观察到肝部分切除后肝再生的损害。脂肪肝更容易受到切除后损伤和失败的影响。其分子机制与核因子-kappa-Bα抑制物(I-kappa-BA)表达增加有关，抑制了核因子-kappa-B(NF-kappa B)的激活，诱导了其靶基因Cyclin D 1和Bc l-xl的表达，增加了对肿瘤坏死因子-α升高所引发的细胞凋亡的敏感性。此外，由于高脂饮食喂养的小鼠由于肥胖增加而导致瘦素水平更高，我们的工作支持了这样的假设，即以前在遗传性肥胖小鼠中看到的再生障碍确实是肝脏脂肪变性而不是瘦素信号中断的结果。总之，饮食中的高脂肪会损害肝脏再生，并通过I-kappa Bα的过度表达和随后的核因子-kappaB抑制而使脂肪性肝脏容易受到更多的损伤。
Despite the growing incidence of obesity, knowledge of how this condition, as well as associated steatosis, affects liver regeneration remains scarce. Many previous studies have used models of steatohepatitis or obesity induced by genetic alterations. In contrast, our studies on liver regeneration have focused on the effects of obesity resulting solely from high amounts of fat in the diet. This model more closely reflects the detrimental effects of dietary habits responsible for increased morbidity due to obesity and its complications in well-developed Western societies. Impairment of liver regeneration was observed after partial hepatectomy in mice fed a high-fat diet. Fatty livers were more susceptible to posthepatectomy damage and failure. The underlying molecular mechanism was associated with increased inhibitor of nuclear factor-kappa B alpha (I kappa Ba) expression, which inhibited nuclear factor-kappa B (NF-kappa B) activation and induction of its target genes, cyclin D 1 and Bcl-xL, increasing sensitivity to apoptosis initiated by elevated tumor necrosis factor-alpha. In addition, since mice fed with a high-fat diet have higher leptin levels caused by increased adiposity, our work supports the hypothesis that the impairment of regeneration previously seen in genetically obese mice indeed results from liver steatosis rather than the disruption of leptin signaling. In conclusion, high fat in the diet impairs liver regeneration and predisposes steatotic livers to increased injury through I kappa B alpha overexpression and subsequent NF-kappa B inhibition.