Harano Yuichi, Yasui Kohichiroh, Toyama Tetsuya, Nakajima Tomoki, Mitsuyoshi Hironori, Mimani Masahito, Hirasawa Tsutomu, Itoh Yoshito, Okanoue Takeshi
Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Liver Int. 2006 Jun;26(5):613-20. doi: 10.1111/j.1478-3231.2006.01265.x.
The fatty liver Shionogi (FLS) mouse, a unique model for nonalcoholic fatty liver disease (NAFLD), is an inbred strain that develops spontaneous hepatic steatosis without obesity or diabetes mellitus. Peroxisome proliferator-activated receptor (PPAR) alpha controls fatty acid metabolism. In the present study, we investigated the effect of fenofibrate, a PPARalpha agonist, on hepatic steatosis in FLS mice.
Thirteen-week-old FLS mice were fed a diet with 0.1% fenofibrate (w/w) for 12 days. The degree of hepatic steatosis was estimated by histological examination and hepatic triglyceride levels. Expression levels of genes involved in fatty acid turnover, including Acox1, Cpt1a, Fabp1, Acadl, and Acadm, were determined by Northern blot analyses. We measured levels of lipid peroxidation, glutathione, and anti-oxidative enzymes, such as superoxide dismutase, catalase, and glutathione peroxidase, in the liver.
Treatment of FLS mice with fenofibrate improved hepatic steatosis by activating expression of genes involved in fatty acid turnover and decreased hepatic lipid peroxidation. Fenofibrate increased the activity of catalase by upregulating its mRNA levels.
Fenofibrate, which is currently used in therapy of hyperlipidemia, might also be useful for treating patients with NAFLD even in cases where NAFLD is not associated with obesity or diabetes mellitus.
脂肪性肝 Shionogi（FLS）小鼠是一种非酒精性脂肪性肝病（NAFLD）的独特模型，是一种近交系，可自发发生肝脂肪变性，且无肥胖或糖尿病。过氧化物酶体增殖物激活受体（PPAR）α 控制脂肪酸代谢。在本研究中，我们研究了 PPARα 激动剂非诺贝特对 FLS 小鼠肝脂肪变性的影响。
给 13 周龄的 FLS 小鼠喂食含 0.1%非诺贝特（w/w）的饲料 12 天。通过组织学检查和肝脏甘油三酯水平评估肝脂肪变性程度。通过 Northern 印迹分析确定参与脂肪酸周转的基因（包括 Acox1、Cpt1a、Fabp1、Acadl 和 Acadm）的表达水平。我们测量了肝脏中的脂质过氧化、谷胱甘肽水平以及超氧化物歧化酶、过氧化氢酶和谷胱甘肽过氧化物酶等抗氧化酶的水平。
非诺贝特治疗 FLS 小鼠可通过激活参与脂肪酸周转的基因表达改善肝脂肪变性，并降低肝脏脂质过氧化。非诺贝特通过上调过氧化氢酶的 mRNA 水平增加其活性。
目前用于治疗高脂血症的非诺贝特，即使在 NAFLD 与肥胖或糖尿病无关的情况下，也可能对治疗 NAFLD 患者有用。
