B28號藥水層萃取物改善倉鼠因高油高膽固醇飲食引起之非酒精性脂肪肝炎

屠智宏

doi:10.6342/NTU201602298

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B28号药水层萃取物改善仓鼠因高油高胆固醇饮食引起之非酒精性脂肪肝炎

Water-soluble fraction of Herb-B28 ameliorates nonalcoholic steatohepatitis (NASH) in high fat/high cholesterol diet-fed hamsters

屠智宏 , 硕士　　导师：吕绍俊　　

繁体中文 DOI： 10.6342/NTU201602298

非酒精性脂肪肝；非酒精性脂肪肝炎；胆固醇；中草药；阴电性低密度脂蛋白 (LDL(-)) ； IL-1β ； Chinese herbal medicine ； Cholesterol ； Electronegative LDL (LDL(-)) ； NAFLD ； NASH ； Neutrophil ； IL-1β

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摘要 │ 参考文献 (96) │ 国际计量

摘要〈TOP〉

非酒精性脂肪肝 (Nonalcoholic fatty liver disease, NAFLD) 是全球最常见的非病毒性慢性肝病，其病程由单纯的肝细胞脂肪油滴堆积，到严重的非酒精性脂肪肝炎 (Nonalcoholic steatohepatitis, NASH)、肝纤维化甚至到肝硬化。至今仍少有药物可以治疗NASH，传统中草药有许多具有保肝作用的药材，其中可能具有减缓或是治疗NASH的功效。实验室学长姐们经过多年的实验筛选，发现中药材B28号药可以改善仓鼠因高油高胆固醇饲料引起之NASH，因此我的实验目的是利用动物实验探讨B28号药的有效成分是在水层或是有机层。
首先在实验I，我将B28号药依序与正己烷、乙酸乙酯及正丁醇进行萃取後取得水层萃取物，并将仓鼠分成4组，为HFC、HFC+B28、HFC+W-a及HFC+W-na，皆喂食含0.5% 胆固醇之高油脂饲料，每天分别灌食蒸馏水、B28号药、经灭菌之水萃物 (W-a) 或未经灭菌之水萃物 (W-na) ，为期6周。结果显示仓鼠灌食B28号药或是水萃物，不论灭菌与否，血浆、肝脏胆固醇以及AST、ALT活性都有下降的趋势，胶体过滤法 (Gel filtration) 分析显示灌食B28号药或水萃物可减少LDL-C，肝脏病理切片分析发现HFC+B28、HFC+W-a及HFC+W-na三组动物的发炎反应以及collagen堆积情形都比HFC组来的减轻，嗜中性白血球浸润也较轻微，显示B28号药及其水萃物的功效并不受到高温高压处理而影响。
为了进一步确定B28号药有效成分位在哪个分层，我们扩大实验规模将仓鼠分成5组进行实验II，每组6~9只动物，分别为HFC、HFC+B28、HFC+W、HFC+3x W及HFC+EA，本次实验经询问专业意见後将萃取方式改为B28号药只以乙酸乙酯进行分配萃取，得到水层以及乙酸乙酯层萃取物。五组仓鼠同样喂食0.5% 胆固醇高油脂饲料并且每日分别灌食蒸馏水、B28号药、B28号药水萃物 (W) 、3倍B28号药水萃物 (3x W) 以及B28号药乙酸乙酯萃取物 (EA)，持续6周。HFC+B28与HFC+3x W两组的血浆、肝脏胆固醇以及AST活性显着低於HFC组，经超高速离心分离脂蛋白，HFC+B28与HFC+3x W两组的LDL-C显着低於HFC组，观察肝脏病理切片，HFC+B28、HFC+3x W两组动物的发炎及collagen堆积情形都比HFC组来的轻微，嗜中性白血球浸润及IL-1β表现也获得改善，代表B28号药与3倍剂量的水萃物能够减缓NASH以及肝纤维化，然而HFC+W及HFC+EA两组并没有出现上述效果，显示改变萃取方式後，水萃物需要使用3倍剂量才会与原药材具有相近之保肝效果。尽管如此透过这两次动物实验可以确认水层含有B28号药的有效成分，有机层萃取物的保肝效果还需要後续实验确认。
实验III为了分析B28号药及其水萃物对於血液阴电性低密度脂蛋白 (LDL(-))含量的影响，将仓鼠分为3组，分别为HFC、HFC+3x B28及HFC+3x W，每组3只动物，每天分别灌食蒸馏水，3倍B28号药 (3x B28) 及3倍B28号药水萃物 (3x W) ，持续灌食6周，前2周喂食chow diet，之後皆改为1 %胆固醇高油脂饲料再喂食4周引起NASH，结果发现HFC+3x B28组的血浆胆固醇及LDL-C含量都显着低於HFC组，同时LDL(-) 的百分比也显着下降，而HFC+3x W组在血浆胆固醇、LDL胆固醇以及LDL(-) 的百分比相较於HFC组都有下降的趋势。最後我们也发现B28号药及其水萃物可以改善大鼠Kupffer cells因LDL(-) 刺激而分泌促发炎激素。未来若能精进萃取方式进而将B28号药的有效成分自水层提取出来，对於发展减缓非酒精性脂肪肝炎之保健食品甚至是新药开发将会有很大的帮助。

并列摘要〈TOP〉

Nonalcoholic fatty liver disease (NAFLD) is one of the most common non-viral chronic liver disease worldwide. NAFLD has a histological spectrum ranging from simple steatosis, nonalcoholic steatohepatitis (NASH), to fibrosis and cirrhosis. However, there is little available therapy for NASH. Some Chinese herbal medicines (CHM) are believed to have liver-protective effects and our previous studies have identified a CHM B28 (B28) has protective effects against high fat/high cholesterol (HFC) diet-induced NAFLD and NASH in the golden Syrian hamster. The aim of this study is to test whether the water-soluble fraction of B28 can also exert protective effects against HFC diet-induced NASH in hamsters.
In animal study I, B28 was sequentially partitioned using solvents with different polarity, including hexane, ethyl acetate and butanol; and the water-soluble extracts were collected. Hamsters were separated into 4 groups. The control group was fed with HFC diets with 0.5% cholesterol and gavaged with distilled water for 6 weeks. The other 3 groups, designated as HFC+B28, HFC+W-a and HFC+W-na were also fed with the HFC diets and gavaged with B28、B28 water-soluble extracts (autoclaved) and B28 water-soluble extracts (non-autoclaved), respectively, for 6 weeks. The results show that B28 and its water-soluble extracts decreased plasma and liver total cholesterol levels and lowered plasma AST and ALT activities compared to the HFC group. Gel filtration analysis revealed that cholesterol levels in LDL fractions is lower in the HFC+B28, HFC+W-a and HFC+W-na groups than in the HFC group. Histopathological analyses of liver sections show that B28 and its water-soluble extracts can alleviate liver inflammation and fibrosis, and also prevent neutrophil infiltration induced by the HFC diet. These results suggest that the liver-protective effects of B28 and its water-soluble extracts are independent of the autoclave sterilization.
In animal study II the B28 was partitioned with ethyl acetate, and the water-soluble and ethyl acetate-soluble extracts were collected. Hamsters were assigned into 5 groups designated as HFC, HFC+B28, HFC+W, HFC+3x W and HFC+EA and all fed with HFC diets with 0.5% cholesterol and gavaged with distilled water, B28、B28 water-soluble extracts, B28 water-soluble extracts (triple-dose) and B28 ethyl acetate extracts, respectively, for 6 weeks. The results show that HFC+B28 and HFC+3x W significantly lowered levels of plasma and liver cholesterol and lowered AST activity compared to the HFC group. Gel filtration and ultracentrifugation analyses of lipoprotein profiles showed that HFC+B28 and HFC+3x W groups have significantly lower levels of cholesterol in LDL fractions. Histopathological analyses of liver sections revealed that HFC+B28 and HFC+3x W groups have minor inflammation and fibrosis state and less neutrophil infiltration compared to the HFC group. The HFC+W and HFC+EA groups have no such effects. These results demonstrate that it will require triple doses of water-soluble extracts to have protective effects against NASH when the partition procedures are changed. Still, our results of these two animal studies indicate that water-soluble extracts preserved the active compounds of B28. 
In animal study III, hamsters were separated into 3 groups designated as HFC, HFC+3x B28 and HFC+3x W. They were gavaged with distilled water, B28 (triple-dose) and B28 water-soluble extracts (triple-dose), respectively, for 6 weeks. All 3 groups were treated with chow diets during the first 2 weeks than the diets were substituted with HFC diets with 1% cholesterol for another 4 weeks. B28 significantly lowered plasma cholesterol and LDL-C levels and decreased plasma LDL(-) contents. B28 water-soluble extracts lowered plasma cholesterol, LDL-C levels and LDL(-) contents to a lesser degree of B28. In vitro studies show that B28 and its water-soluble extracts lowered the LDL(-)-induced secretion of proinflammatory cytokines by rat Kupffer cells. In the future, we aim to obtain the active compounds from the water-soluble fraction of B28 by refining the partition procedures, and it will be of great help for new drug development against NASH.

参考文献 ( 96 ) 〈TOP〉

Alkhouri, N., Morris-Stiff, G., Campbell, C., Lopez, R., Tamimi, T. A., Yerian, L., Zein, N. N., and Feldstein, A. E. (2012). Neutrophil to lymphocyte ratio: a new marker for predicting steatohepatitis and fibrosis in patients with nonalcoholic fatty liver disease. Liver Int 32, 297-302.
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Anstee, Q. M., Targher, G., and Day, C. P. (2013). Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Nat Rev Gastroenterol Hepatol 10, 330-344.
连结：
Assmann, G. and Gotto, A. M. (2004). HDL cholesterol and protective factors in atherosclerosis. Circulation 109, III-8 – III-14.
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Barter, P. (2005). The role of HDL-cholesterol in preventing atherosclerotic disease. Eur Heart J Suppl. 7, F4-F8
连结：
Bieghs, V., Verheyen, F., van Gorp, P. J., Hendrikx, T., Wouters, K., Lutjohann, D., Giibels, M. J., Febbraio, M., Binder, C. J., Hofker, M. H., and Shiri-Sverdlov, R. (2012). Internalization of modified lipids by CD36 and SR-A leads to hepatic inflammation and lysosomal cholesterol storage in Kupffer cells. PloS One 7, e34378.
连结：

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