本文選題：非酒精性脂肪肝　切入點：肝細胞核因子4α　出處：《南京醫(yī)科大學》2016年碩士論文　論文類型：學位論文

【摘要】：非酒精性脂肪肝(Nonalcoholic fatty liver disease, NAFLD)是目前最常見的代謝性疾病之一,其發(fā)病率約為10-24%,且有低齡發(fā)病的趨勢,因此,對脂肪肝的防治研究不斷得到醫(yī)學界的重視。肝細胞核因子4α (Hepatocyte nuclear factor 4-alpha, HNF4α)是一種核轉(zhuǎn)錄因子,在調(diào)控肝臟脂肪代謝和糖異生等方面扮演重要的角色。 HNF4α能夠增加脂肪酸氧化、促進膽汁酸的分泌、增加肝臟極低密度脂蛋白(Very low density lipoprotein, VLDL)和甘油三酯(Triglyceride, TG)向血漿運輸。許多報道證實HNF4α功能性的缺失導致肝臟脂肪性病變,例如在NAFLD患者中,約有半數(shù)的患者表現(xiàn)出HNF4α突變或缺失。然而HNF4α在高能量攝入誘導的NAFLD中的調(diào)節(jié)機制有待進一步研究。本課題中,我們利用高脂飲食喂飼小鼠建立脂肪肝模型,發(fā)現(xiàn)高脂飲食誘導HNF4α胞質(zhì)的滯留,抑制了肝臟載脂蛋白B (ApolipoproteinB, ApoB)的表達水平,可能是高脂飲食阻礙VLDL的分泌的原因。我們分離小鼠原代肝細胞在離體條件下模擬NAFLD的內(nèi)環(huán)境,從一系列刺激因素中篩選發(fā)現(xiàn),脂多糖(Lipopolysaccharide, LPS)、棕櫚酸(Palmitate, PA)和腫瘤壞死因子α (Tumor necrosis factor-α, TNF-α)能夠誘導HNF4α胞質(zhì)的滯留,從而證明了高脂、炎癥對HNF4α的功能影響。進一步研究發(fā)現(xiàn),高脂和炎癥激活肝臟中蛋白激酶C (Protein kinase C, PKC), PKC通過磷酸化介導HNF4α胞質(zhì)滯留,很可能是阻礙HNF4α對下游ApoB轉(zhuǎn)錄調(diào)控的原因。我們揭示了炎癥、高脂／PKC/HNF4α的脂質(zhì)代謝調(diào)節(jié)通路,從而為NAFLD的治療提供新的思路。
[Abstract]:Nonalcoholic fatty liver disease (NAFLDs) is one of the most common metabolic diseases. Its incidence is about 10-240.It has a tendency to develop at a young age. The study of prevention and treatment of fatty liver has been paid more and more attention in the field of medicine. Hepatocyte nuclear factor 4-alpha (HNF4 偽) is a kind of nuclear transcription factor, which plays an important role in regulating liver fat metabolism and glycosylation. HNF4 偽 can increase fatty acid oxidation. Promote the secretion of bile acids and increase the transport of very low density lipoprotein (VLDLs) and triglyceride (TGs) from the liver to the plasma. Many reports have shown that the absence of HNF4 偽 function leads to hepatic fatty lesions, such as in patients with NAFLD. About half of the patients showed mutations or deletions of HNF4 偽. However, the regulatory mechanism of HNF4 偽 in high-energy intake induced NAFLD needs further study. In this study, we used high-fat diet to establish fatty liver model in mice. It was found that high fat diet induced the retention of HNF4 偽 cytoplasm and inhibited the expression of apolipoprotein B protein B (ApoB) in the liver, which may be the reason that high fat diet blocked the secretion of VLDL. We isolated primary mouse hepatocytes in vitro to mimic the internal environment of NAFLD. It was found that lipopolysaccharide, lipopolysaccharide, palmitate (PAA) and tumor necrosis factor 偽 -Tumor necrosis factor- 偽 (TNF- 偽) could induce the retention of HNF4 偽 cytoplasm from a series of stimuli, thus proving the effect of hyperlipidemia and inflammation on the function of HNF4 偽. Hyperlipidemic and inflammatory activation of protein kinase C protein kinase, PKC, PKC through phosphorylation may inhibit the regulation of HNF4 偽 on downstream ApoB transcription. We have revealed the lipid metabolism regulation pathway of high fat / high fat / PKC / HNF4 偽 in the liver. So as to provide a new idea for the treatment of NAFLD.
【學位授予單位】：南京醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2016
【分類號】：R575.5

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本文編號：1618910