合成性類黃酮衍生物在抑制肝細胞脂肪堆積之評估

當脂質過度累積在肝臟即造成脂肪肝，非酒精性脂肪肝 (NAFLD) 已成為全球最常見的肝病之一，但臨床上仍未出現具專一性且公認可有效治療NAFLD並伴隨較低副作用之藥物。近年來查耳酮及其衍生物已被許多研究指出具豐富的生物活性，還可緩和胰島素阻抗及改善代謝問題。因此本論文研究目的為針對49種查耳酮化合物，進行肝細胞降脂功效篩選，並探討其影響之分子機制。透過細胞存活率及脂質染色實驗結果顯示，編號16、19及28查耳酮化合物具較佳降脂效果，且對肝細胞存活率造成較少影響。天然萃取的查耳酮Flavokawain B需使用高於查耳酮化合物之作用濃度，才得以產生顯著程度相似的降脂效果。產生脂肪堆積之HepG2細胞經過編號16、19化合物處理後，調控脂質氧化作用 (β-oxidation) 之轉錄因子PPARα還有其下游CPT1的mRNA與蛋白質表現量顯著提升，且代表脂肪酸氧化的指標產物酮體β-hydroxybutyrate濃度也明顯增加；編號19化合物同時也可抑制調節脂質形成的轉錄因子SREBP1與相關基因FAS、ACC、DGAT和GPAT的mRNA表現量。在分子機轉上，FKB則是主要作用於抑制脂質形成的部分。綜合以上實驗結果，編號19化合物有抑制脂質形成相關基因表現的效果；而編號16及19化合物主要調控的分子機轉還有顯著提升脂肪酸進行β-oxidation。本篇實驗篩選出的查耳酮化合物藉由增加脂質氧化作用，將囤積的脂肪轉換成能量，以此減少原有的脂質累積。加上化學合成產量較高、成本較低的優點，本研究中的化學合成性查耳酮在將來極可能成為非常具有發展潛力的NAFLD治療藥物之一。

關鍵字

非酒精性脂肪肝；查耳酮

並列摘要

Excessive lipid accumulation in the liver has been proposed to cause fatty liver disease. Non-alcoholic fatty liver disease (NAFLD) is a common chronic metabolic diseases and which is still lack of specific treatment with remarkable improvement in liver histology. In recent years, chalcones have been indicated that owning various biological activities. It also have the effect on alleviating insulin resistance and improving the metabolic disorder. In our study, we are looked for potential therapy for NAFLD. We tried to screen out the chalcone compounds with ability to inhibit NAFLD among 49 synthetic chalcone compounds. MTT assay and Oil red O staining data indicated that compound 16, 19, 28 were the top three chalcones that decreased the lipid accumulation in hepatic cell with less cytotoxicity. The botanical extract chalcone, Flavokawain B (FKB) needed the higher working concentration to decrease the lipid accumulation. The mRNA and protein levels of PPARα and CPT1 which directly related to fatty acid β-oxidation were significantly increased after the HepG2 cell treated with the compounds 16 and 19. The concentration of β-hydroxybutyrate, which is the marker of hepatocyte fatty acid β-oxidation level in HepG2 cell, increased after treated with the chalcone compounds. The HepG2 cell mRNA level of SREBP1, the transcription factor of lipid synthesis and DGAT1, ACC, GPAT and FAS which are the genes related to lipogenesis were decreased after compound 19 treatment. The moleculars that FKB mainly affect on was the genes related to lipid synthesis. In summary, compound 19 can inhibit the genes expression related to lipid synthesis. Furthermore, the enhancing of hepatocyte β-oxidation level was the main pathway that compound 16 and 19 involved in reducing lipid accumulation. To date, a lot of studies also consider the increasing of β-oxidation as a new target to alleviate NAFLD. Moreover, the advantage of chemical synthesis compound is higher production with less cost. We supposed that the synthetic chalcone compounds might be valuable for being the therapy of modulating hepatic lipid metabolism and NAFLD.

並列關鍵字

NAFLD ； chalcone

參考文獻

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