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標題: 酒精對細胞及小鼠之傷害以及菸鹼醯胺之保護作用
The deleterious effects of ethanol and the protective roles of nicotinamide
作者: 陳妤瑄
Chen, Yu-Hsuan
關鍵字: ethanol
liver injury
cell senescence
oxidative stress
ethanol-induced hepatosteatosis
出版社: 食品暨應用生物科技學系所
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摘要: 本論文主要是探討酒精造成的肝損傷及細胞老化,並了解菸鹼醯胺可能之保護作用。 許多的研究指出,酒精對老年人造成較大傷害,其原因可能是因為肝臟的抗氧化能力下降,使得肝臟無法修復酒精所造成的傷害。 因為老化促進小鼠在生命早期就會出現老化的現象,所以本研究用老化促進小鼠動物模式來探討酒精對老年人造成的肝損傷。 結果顯示酒精會增加血清轉胺酶活性,增加肝臟中丙二醛及羰基化蛋白含量,並降低肝臟中穀胱甘肽過氧化酶,過氧化氫酶,和超氧化物歧化酶的活性。 蘇木素及伊紅染色顯示中度以上的脂肪浸潤但沒有纖維化的情形。 餵食高劑量(500 mg/kg BW)菸鹼醯胺可明顯改善餵食酒精老鼠的老化指數,減少氧化壓力及抑制CYP2E1蛋白的表現。 由於酒精是主要在肝臟代謝的毒性物質,很容易造成脂肪肝, 因此本研究用C57BL/6J品系的小鼠及人類肝癌細胞株HepG2細胞來探討C/EBP α、β及δ在酒精誘發脂肪肝的表現。 結果顯示C/EBP δ會在酒精誘發脂肪肝的早期開始表現,顯示其可能作為治療酒精性脂肪肝的一個指標。 因為酒精會造成老化促進小鼠的氧化壓力,而菸鹼醯胺有改善小鼠的老化指數的現象,於是本研究接著嘗試建立一個低劑量、長時間的酒精處理的細胞模式,以模擬在體內長期氧化壓力的形式,並探討營養素的保護作用。 結果顯示長期低劑量的酒精處理,會造成細胞生長停止並出現細胞老化的形態,包括細胞外形呈扁平狀、老化相關的半乳糖酶表現呈陽性、生長曲線變得平緩,伴隨細胞週期中G1 細胞增加。這些現象可能與NAD+/NADH的比值下降及還原態榖胱甘肽減少有關。 菸鹼醯胺表現出明顯的抗老化作用,包括延長生長代數、維持年輕化細胞型態、減少老化相關的半乳糖酶活性及維持正常的細胞週期。 雖然菸鹼醯胺抗酒精促老化的機制尚未釐清,而這些抗老化作用可能與菸鹼醯胺調節細胞週期、增加NAD+/NADH的比值及避免還原態榖胱甘肽減少有關。 總之,本論文證實酒精會造成細胞老化,氧化壓力及脂肪肝,而且菸鹼醯胺扮演著一個重要的保護角色。
This dissertation is concerned with the effect of ethanol on liver injury, cell senescence and the possible protective roles of nicotinamide (NAM). Several studies have shown that the greater susceptibility of older people to the adverse effects of ethanol may be due to the depletion of hepatic antioxidants and a resulting decrease in the ability of the liver to recover from ethanol-induced damage. Because senescence-accelerated-prone 8 mice (SAMP8) begin to show signs of aging in their early life, we herein employed the SAMP8 mice as animal model for studying ethanol-induced liver injury in the elderly. Results showed that ethanol elevated activity of serum aminotransferase. Ethanol also enhanced the formation of malondialdehyde (MDA) and protein carbonyls in the liver, whereas ethanol treatment resulted in significantly lower activity of hepatic glutathione peroxidase (GPx), catalase and superoxide dismutase (SOD). Hematoxylin and eosin staining on the liver sections indicated moderate to severe fatty infiltration but not fibrosis. Administration of high NAM (500 mg/kg BW) led to markedly decreased the aging score, diminished the oxidative stress and to inhibit protein expression of CYP2E1 in the ethanol-fed mice. A long term ethanol administration induce steatosis of mice liver, in order to elucidate the mechanisms of ethanol-induced hepatosteatosis, both the in vivo and in vitro effect of ethanol on the expression of C/EBP α, β and δ in male C57BL/6J mice and HepG2 cells were conducted. The results have shown that C/EBP δ expression appears to play an important role in the early phase of ethanol-induced hepatosteatosis in mice and in ethanol-treated HepG2 cells. Thus, C/EBP δ might be a therapeutic target in alcoholic hepatosteatosis. The previous results have shown that NAM led to markedly decreased aging score in ethanol-treated mice, herein we established a low-concentration and long-term ethanol treatment model to mimic the prolonged oxidative stress in vitro and to elucidate the protective role of NAM. We found that the prolonged low concentration of ethanol treatment induced cell cycle arrest and senescent-like morphology. These cells exhibited signs of aging as indicated by large, flattened morphology, senescence-associated β-galactosidase (SA-β-gal) staining and decreased additional population doubling level (PDL). This was accompanied by a significant increase in the percentage of G1 cells. These effects of ethanol may be related to the decreased NAD+/NADH ratio and GSH depletion. NAM exerted a clear anti-aging effect by increasing PDL, juvenating cell morphology, decreasing SA-β-gal activity and showing the same cell cycle profile as control. Although its protective mechanism is still obscure, NAM may delay ethanol-induced cell senescence by, at least in part, regulation of the cell cycle and by increasing NAD+/NADH and GSH level. In summary, the obtained results demonstrate that ethanol induces senescence, oxidative stress and hepatosteatosis both in in vivo and in vitro while that NAM exerts an important role in protection.
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