HNF4α功能障碍促进非酒精性脂肪肝发生发展的机制研究

发布时间：2018-03-16 07:25

本文选题：非酒精性脂肪肝　切入点：肝细胞核因子4α　出处：《南京医科大学》2016年硕士论文　论文类型：学位论文

【摘要】：非酒精性脂肪肝(Nonalcoholic fatty liver disease, NAFLD)是目前最常见的代谢性疾病之一,其发病率约为10-24%,且有低龄发病的趋势,因此,对脂肪肝的防治研究不断得到医学界的重视。肝细胞核因子4α (Hepatocyte nuclear factor 4-alpha, HNF4α)是一种核转录因子,在调控肝脏脂肪代谢和糖异生等方面扮演重要的角色。 HNF4α能够增加脂肪酸氧化、促进胆汁酸的分泌、增加肝脏极低密度脂蛋白(Very low density lipoprotein, VLDL)和甘油三酯(Triglyceride, TG)向血浆运输。许多报道证实HNF4α功能性的缺失导致肝脏脂肪性病变,例如在NAFLD患者中,约有半数的患者表现出HNF4α突变或缺失。然而HNF4α在高能量摄入诱导的NAFLD中的调节机制有待进一步研究。本课题中,我们利用高脂饮食喂饲小鼠建立脂肪肝模型,发现高脂饮食诱导HNF4α胞质的滞留,抑制了肝脏载脂蛋白B (ApolipoproteinB, ApoB)的表达水平,可能是高脂饮食阻碍VLDL的分泌的原因。我们分离小鼠原代肝细胞在离体条件下模拟NAFLD的内环境,从一系列刺激因素中筛选发现,脂多糖(Lipopolysaccharide, LPS)、棕榈酸(Palmitate, PA)和肿瘤坏死因子α (Tumor necrosis factor-α, TNF-α)能够诱导HNF4α胞质的滞留,从而证明了高脂、炎症对HNF4α的功能影响。进一步研究发现,高脂和炎症激活肝脏中蛋白激酶C (Protein kinase C, PKC), PKC通过磷酸化介导HNF4α胞质滞留,很可能是阻碍HNF4α对下游ApoB转录调控的原因。我们揭示了炎症、高脂／PKC/HNF4α的脂质代谢调节通路,从而为NAFLD的治疗提供新的思路。
[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 伪) is a kind of nuclear transcription factor, which plays an important role in regulating liver fat metabolism and glycosylation. HNF4 伪 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 伪 function leads to hepatic fatty lesions, such as in patients with NAFLD. About half of the patients showed mutations or deletions of HNF4 伪. However, the regulatory mechanism of HNF4 伪 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 伪 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 伪 -Tumor necrosis factor- 伪 (TNF- 伪) could induce the retention of HNF4 伪 cytoplasm from a series of stimuli, thus proving the effect of hyperlipidemia and inflammation on the function of HNF4 伪. Hyperlipidemic and inflammatory activation of protein kinase C protein kinase, PKC, PKC through phosphorylation may inhibit the regulation of HNF4 伪 on downstream ApoB transcription. We have revealed the lipid metabolism regulation pathway of high fat / high fat / PKC / HNF4 伪 in the liver. So as to provide a new idea for the treatment of NAFLD.
【学位授予单位】：南京医科大学
【学位级别】：硕士
【学位授予年份】：2016
【分类号】：R575.5

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