Lee Seunghyun, Kwak Jae-Hwan, Kim Sou Hyun, Jeong Tae Bin, Son Seung Won, Kim Joung-Hee, Lim Yong, Cho Joon-Yong, Hwang Dae Youn, Kim Kil Soo, Jung Young-Suk
1College of Pharmacy, Pusan National University, Busan, South Korea.
2College of Pharmacy, Brain Busan 21 Plus Program, Kyungsung University, Busan, South Korea.
Lab Anim Res. 2019 Aug 17;35:15. doi: 10.1186/s42826-019-0016-y. eCollection 2019.
Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease worldwide. It is characterized by the accumulation of lipids without alcohol intake and often progresses to non-alcoholic steatohepatitis (NASH), liver fibrosis, and end-stage liver diseases such as cirrhosis or cancer. Although animal models have greatly contributed to the understanding of NAFLD, studies on the disease progression in humans are still limited. In this study, we used the recently reported high-fat L-methionine-defined and choline-deficient (HFMCD) diet to rapidly induce NASH and compared the responses to HFMCD in ICR mice from three different countries: Korea (supplied by the National Institute of Food and Drug Safety Evaluation), USA, and Japan during 6 weeks. Feeding HFMCD did not cause significant differences in weight gain in comparison with mice fed control diet. Relative weight of the liver increased gradually, while the relative weight of the kidneys remained unchanged. The parameters of liver injury (serum activities of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase) increased rapidly from 1 week and remained elevated for as long as 6 weeks. Histopathological analysis showed that the accumulation of hepatic lipids induced by HFMCD was prominent at 1 week after diet supplementation and increased further at 6 weeks. Inflammatory markers were significantly increased in a time-dependent manner by HFMCD. The mRNA levels of TNF-α and IL-6 were elevated approximately 15-fold relative to control diet and that of IL-1β was increased more than 20-folds at 6 week after the onset of HFMCD intake. In addition, mRNA expression of fibrosis markers such as α-SMA, TGFβ1, and Col1a1 were also significantly increased at 6 week. In summary, the responses of Korl:ICR mice by intake of HFMCD diet were similar to those of ICR mice from other sources, which suggests that Korl:ICR mice is also a useful resource to study the pathogenesis of diet-induced NAFLD.
非酒精性脂肪性肝病（NAFLD）是全球慢性肝病的主要病因。其特征是在无酒精摄入的情况下脂质蓄积，且常进展为非酒精性脂肪性肝炎（NASH）、肝纤维化以及诸如肝硬化或癌症等终末期肝病。尽管动物模型对理解NAFLD有很大帮助，但关于人类疾病进展的研究仍然有限。在本研究中，我们使用最近报道的高脂肪甲硫氨酸限定和胆碱缺乏（HFMCD）饮食快速诱导NASH，并比较了来自三个不同国家（韩国（由国家食品药品安全评价研究院提供）、美国和日本）的ICR小鼠在6周内对HFMCD的反应。与喂食对照饮食的小鼠相比，喂食HFMCD并未导致体重增加有显著差异。肝脏相对重量逐渐增加，而肾脏相对重量保持不变。肝损伤参数（血清丙氨酸氨基转移酶、天冬氨酸氨基转移酶和乳酸脱氢酶活性）从第1周开始迅速升高，并持续升高长达6周。组织病理学分析表明，HFMCD诱导的肝脏脂质蓄积在饮食补充后1周时显著，在6周时进一步增加。HFMCD以时间依赖性方式显著增加炎症标志物。在开始摄入HFMCD 6周后，TNF-α和IL-6的mRNA水平相对于对照饮食升高约15倍，IL-1β的mRNA水平增加超过20倍。此外，在6周时，诸如α-SMA、TGFβ1和Col1a1等纤维化标志物的mRNA表达也显著增加。总之，Korl:ICR小鼠摄入HFMCD饮食后的反应与其他来源的ICR小鼠相似，这表明Korl:ICR小鼠也是研究饮食诱导的NAFLD发病机制的有用资源。
