本文選題：骨保護(hù)素 + 非酒精性脂肪肝�。� 參考：《重慶醫(yī)科大學(xué)》2017年博士論文

【摘要】：第一部分OPG在NAFLD動(dòng)物模型和病人中的表達(dá)目的:探索OPG在NAFLD動(dòng)物模型和NAFLD病人中的變化,初步了解OPG與NAFLD之間的關(guān)系。方法:采用定量PCR法檢測(cè)c57普食喂養(yǎng)雄性小鼠(20周齡)、HFD小鼠(8周齡開始喂養(yǎng)高脂12周)、ob/ob(普食喂養(yǎng),20周齡)、db/db(普食喂養(yǎng),20周齡)、脂聯(lián)素基因敲除小鼠,NAFLD病人肝臟中OPG m RNA的表達(dá)情況。通過western blot方法檢測(cè)c57、HFD、ob/ob、db/db,NAFLD病人肝臟中OPG蛋白表達(dá)情況。免疫組化分析NAFLD病人和正常人肝臟中OPG蛋白的表達(dá)。利用不同濃度的葡萄糖和FFAs刺激L02細(xì)胞后,測(cè)定OPG m RNA的變化。應(yīng)用定量PCR方法測(cè)定不同喂養(yǎng)狀態(tài)下c57小鼠肝臟中OPG m RNA的表達(dá)。結(jié)果:在NAFLD動(dòng)物模型和NAFLD病人中,OPG m RNA和蛋白含量均顯著降低(P0.05),葡萄糖可以呈劑量依賴性的刺激OPG m RNA的表達(dá),而FFAs則抑制OPG m RNA的表達(dá)。在空腹時(shí),OPG m RNA表達(dá)升高,再喂養(yǎng)后OPG m RNA表達(dá)降低。結(jié)論:OPG與NAFLD的發(fā)生發(fā)展密切相關(guān)。第二部分體外改變OPG表達(dá)影響肝細(xì)胞甘油三酯的含量目的:體外證實(shí)OPG對(duì)肝細(xì)胞甘油三酯的影響。方法:通過構(gòu)建OPG過表達(dá)或抑制腺病毒,感染L02細(xì)胞后,利用FFAs誘導(dǎo)肝細(xì)胞脂肪變性。通過油紅O染色觀察L02細(xì)胞脂滴變化情況,甘油三酯測(cè)定試劑盒測(cè)定肝細(xì)胞中TG的含量,PCR法測(cè)定甘油三酯代謝相關(guān)基因FATP2、FATP4、FATP5、CD36、SREBP1c、FAS、ACC、SCD-1、ch REBP、PPARα、Cpt-1a、Mcad、MTTP、LXR、PXR、RXR、PPARγ等m RNA的變化,western blot法測(cè)定甘油三酯代謝相關(guān)基因SREBP1c、ACC、FAS、CD36、PPARγ等蛋白的變化,western blot法篩選PKA、Akt、JNK、P38、ERK等信號(hào)通路的變化。結(jié)果:成功構(gòu)建OPG過表達(dá)和抑制腺病毒。與對(duì)照組相比較,OPG過表達(dá)組肝細(xì)胞脂滴的數(shù)量及甘油三酯的含量顯著升高(P0.05);且脂肪酸攝取相關(guān)基因CD36顯著升高,而脂肪酸合成相關(guān)基因SREBP1c、FAS、ACC、SCD-1,脂肪酸β氧化相關(guān)基因PPARα、Cpt-1a、Mcad,VLDL分泌相關(guān)基因MTTP等無明顯變化。其次,OPG過表達(dá)組核受體基因PPARγ表達(dá)明顯升高,而p-ERK的活性降低。然而,與對(duì)照組比較,OPG表達(dá)降低則會(huì)抵抗FFAs所誘導(dǎo)的肝細(xì)胞脂肪聚集,肝細(xì)胞中TG含量降低。脂肪酸攝取相關(guān)基因CD36顯著降低,而脂肪酸合成相關(guān)基因SREBP1c、FAS、ACC、SCD-1,脂肪酸β氧化相關(guān)基因PPARα、Cpt-1a、Mcad,VLDL分泌相關(guān)基因MTTP等變化不明顯。OPG抑制降低了核受體基因PPARγ的表達(dá),增加了p-ERK的活性。結(jié)論:體外,OPG促進(jìn)肝細(xì)胞甘油三酯聚集,這一過程可能與CD36和PPARγ的表達(dá)密切相關(guān)。第三部分OPG基因敲除小鼠抵抗高脂飲食誘導(dǎo)的肝臟脂肪變性目的:通過研究OPG基因敲除小鼠,在體內(nèi)明確OPG調(diào)控肝臟甘油三酯代謝的機(jī)制。方法:以雜合子與雜合子配種的方式大量繁殖OPG基因敲除小鼠,獲得足夠雄性野生型和純合子小鼠后,在8周齡開始高脂喂養(yǎng)12周,分成WT-SD、OPG-/--SD、WT-HFD、OPG-/--HFD組。每周測(cè)定各組小鼠的體重、攝食等,在20周齡時(shí)行GTT、ITT等實(shí)驗(yàn),通過眼球取血測(cè)定血清生化指標(biāo),取肝臟做組織病理切片,油紅O染色觀察肝臟脂滴多少,HE染色觀察肝細(xì)胞脂肪變性情況,試劑盒測(cè)定肝臟甘油三酯等含量。提取肝臟組織RNA和蛋白做基因表達(dá)檢測(cè),PCR法測(cè)定甘油三酯代謝相關(guān)基因FATP2、FATP4、FATP5、CD36、SREBP1c、FAS、ACC、SCD-1、ch REBP、PPARα、Cpt-1a、Mcad、MTTP、LXR、RXR、PXR、FXR、PPARγ等m RNA的變化,western blot法測(cè)定甘油三酯代謝相關(guān)基因PPARγ、CD36、p-ERK等蛋白的變化。結(jié)果:OPG基因敲除小鼠體重明顯低于WT小鼠,而攝食無明顯變化。GTT、ITT實(shí)驗(yàn)顯示OPG基因敲除小鼠能抵抗高脂誘導(dǎo)的胰島素抵抗。血清學(xué)檢測(cè)顯示,高脂喂養(yǎng)之后,AST、ALT、TG、TC、FFA、GLU等明顯升高,而OPG基因敲除組則低于WT對(duì)照組(P0.05)。肝臟組織切片顯示高脂喂養(yǎng)后,小鼠肝臟中脂滴明顯增多,HE染色結(jié)果顯示小鼠肝臟發(fā)生明顯脂肪變性、空泡顯著增多,但是OPG-/--HFD明顯好于WT-HFD組。OPG-/-組肝臟甘油三酯含量低于WT組。OPG基因敲除組肝細(xì)胞脂肪酸攝取相關(guān)基因CD36、FATP2、FATP5表達(dá)明顯降低,而脂肪酸合成相關(guān)基因SREBP1c、FAS、ACC、SCD-1,脂肪酸β氧化相關(guān)基因PPARα、Cpt-1a、Mcad,VLDL分泌相關(guān)基因MTTP等無明顯變化。OPG-/-組小鼠肝臟PPARγ表達(dá)降低,而p-ERK活性增強(qiáng)。結(jié)論:體內(nèi),OPG基因敲除小鼠能夠明顯抵抗高脂飲食喂養(yǎng)誘導(dǎo)的肝臟脂肪變性,可能與脂肪酸攝取相關(guān)基因的表達(dá)變化密切相關(guān)。第四部分OPG調(diào)控甘油三酯代謝的機(jī)制目的:探索OPG調(diào)控肝臟甘油三酯代謝的分子機(jī)制。方法:首先利用原代肝細(xì)胞分離術(shù),驗(yàn)證OPG過表達(dá)對(duì)c57原代肝細(xì)胞中TG及脂肪酸攝取相關(guān)基因CD36,核受體基因PPARγ,p-ERK等的影響。然后分離培養(yǎng)OPG-/-小鼠原代肝細(xì)胞,分析其與WT對(duì)照組中肝細(xì)胞內(nèi)TG含量及脂肪酸攝取相關(guān)基因CD36,核受體基因PPARγ,p-ERK等的影響。進(jìn)一步,利用CD36-/-原代肝細(xì)胞培養(yǎng),驗(yàn)證OPG是否通過CD36來調(diào)控肝細(xì)胞中TG的含量。最后通過使用PPARγ抑制劑GW9662、ERK抑制劑SCH772984驗(yàn)證OPG是否通過p-ERK、PPARγ調(diào)控CD36的表達(dá)。結(jié)果:c57原代肝細(xì)胞經(jīng)OPG-Fc處理之后,細(xì)胞內(nèi)TG含量增多,脂肪酸攝取基因CD36表達(dá)增加,核受體基因PPARγ表達(dá)升高,而p-ERK活性降低。OPG-/-原代肝細(xì)胞較WT對(duì)照組,細(xì)胞內(nèi)TG減少,脂肪酸攝取基因CD36表達(dá)降低,核受體基因PPARγ表達(dá)下降,而p-ERK活性增強(qiáng)。在CD36-/-原代中,OPG-Fc則不能增加細(xì)胞內(nèi)TG含量。應(yīng)用PPARγ抑制劑GW9662后,OPG-Fc不能增加CD36的表達(dá)。預(yù)先處理ERK抑制劑SCH772984后,OPG-Fc不能增加PPARγ、CD36的表達(dá)。結(jié)論:OPG通過ERK-PPARγ-CD36軸調(diào)控肝臟甘油三酯的含量。
[Abstract]:Part one OPG expression in NAFLD animal models and patients: To explore the changes in OPG in NAFLD animal models and NAFLD patients and to preliminarily understand the relationship between OPG and NAFLD. Methods: the quantitative PCR method was used to detect the male mice (20 weeks old) of C57 universal food (20 weeks old), HFD mice (8 weeks of age to feed high fat 12 weeks), ob/ob (general feeding, 20 weeks old), D B/db (feeding, 20 weeks old), the expression of OPG m RNA in the liver of NAFLD patients with adiponectin gene knockout mice. The expression of C57, HFD, ob/ob, db/db, NAFLD patients' liver was detected by Western blot method. The changes of OPG m RNA were measured after the stimulation of L02 cells. The expression of OPG m RNA in the liver of C57 mice under different feeding States was measured by quantitative PCR. Expression of PG m RNA. The expression of OPG m RNA increased at the empty stomach and OPG m RNA expression decreased after refeeding. Conclusion: OPG and NAFLD are closely related. The second part changes OPG expression in vitro to influence the content of triglycerides in liver cells: in vitro, the effect on hepatocyte glycerol three ester. Method: through construction of overexpression or inhibition Adenovirus, infected with L02 cells, used FFAs to induce fatty degeneration of liver cells. The changes of lipid droplets in L02 cells were observed by oil red O staining. The content of TG in hepatocytes was determined by triglyceride determination kit. PCR method was used to determine triglyceride metabolism related genes FATP2, FATP4, FATP5, CD36, SREBP1c, FAS. PXR, RXR, PPAR gamma and other m RNA changes. Western blot method was used to determine the changes in triglyceride metabolism related genes SREBP1c, ACC, FAS, CD36, PPAR gamma and other proteins. The content of the number and triglyceride increased significantly (P0.05), and the fatty acid uptake related gene CD36 increased significantly, while the fatty acid synthesis related genes SREBP1c, FAS, ACC, SCD-1, fatty acid beta oxidation related genes PPAR a, Cpt-1a, Mcad, VLDL secreted related genes were not significantly changed. Secondly, the gene expression of nuclear receptor gene in the OPG overexpressed group was expressed clearly. Compared with the control group, the decrease of OPG expression resisted the liver cell fat aggregation induced by FFAs, the decrease of TG content in the hepatocytes and the decrease of the fatty acid uptake related gene CD36, and the fatty acid synthesis related genes SREBP1c, FAS, ACC, SCD-1, and fatty acid beta oxidation related genes PPAR a, Cpt-1a, Mcad, FFAs, compared with the control group. The changes of L secretory related gene MTTP do not obviously decrease the expression of PPAR gamma and increase the activity of p-ERK. Conclusion: in vitro, OPG promotes triglyceride aggregation in liver cells, this process may be closely related to the expression of CD36 and PPAR gamma. The third part of OPG knockout mice resists the liver fatty changes induced by high fat diet. Objective: To investigate the mechanism of OPG regulation of triglyceride metabolism in the liver by studying OPG knockout mice. Methods: multiply OPG knockout mice with heterozygotes and heterozygotes, and get enough male wild type and homozygote mice for 12 weeks at 8 weeks of age, and are divided into WT-SD, OPG-/--SD, WT-HFD, OPG-/. Group --HFD. Every week, the weight of mice in each group was measured, feeding and so on. At the age of 20 weeks, GTT, ITT and other experiments were carried out. The serum biochemical indexes were measured by taking blood from the eyeball, taking the liver to make histopathological sections, using the oil red O staining to observe the liver lipid droplets, the HE staining to observe the liver cell fatty degeneration, the determination of liver triglyceride content by the kit and the extraction of liver group. RNA and protein were detected by gene expression, and the changes of triglyceride metabolism related genes such as FATP2, FATP4, FATP5, CD36, SREBP1c, FAS, ACC, SCD-1, CH REBP were measured by PCR. The weight of the knockout mice was significantly lower than that of the WT mice, while the feeding was not significantly changed by.GTT. The ITT test showed that the OPG gene knockout mice could resist high fat induced insulin resistance. The serological test showed that after high fat feeding, AST, ALT, TG, TC, FFA, GLU, and so on were significantly higher, while the OPG gene knockout group was lower than that of the WT control group. The liver tissue section showed high After fat feeding, the lipid droplets in the liver of mice increased obviously. The results of HE staining showed that the liver of mice had obvious fatty degeneration and vacuoles significantly increased, but the content of triglyceride in the liver of group.OPG-/- was better than that of group.OPG-/- in group WT-HFD, and the expression of fatty acid related genes CD36, FATP2 and FATP5 decreased significantly in the group of.OPG gene knockout group WT. Fatty acid synthesis related genes SREBP1c, FAS, ACC, SCD-1, fatty acid beta oxidation related gene PPAR alpha, Cpt-1a, Mcad, VLDL secretion related gene MTTP and so on, the expression of PPAR gamma in the liver of.OPG-/- mice decreased, but p-ERK activity was enhanced. Sex may be closely related to the changes in the expression of fatty acid uptake related genes. Fourth the mechanism of regulating triglyceride metabolism by OPG: To explore the molecular mechanism of OPG regulation of triglyceride metabolism in the liver. Methods: first of all, primary hepatocyte isolation was used to verify the TG and fatty acid uptake related gene CD3 in C57 primary hepatocytes by OPG overexpression. 6, the effect of nuclear receptor gene PPAR gamma, p-ERK and so on. Then, the primary hepatocytes of OPG-/- mice were isolated and cultured, and the effects of TG content and fatty acid uptake related gene CD36, nuclear receptor gene PPAR gamma, p-ERK and so on in the liver cells of the WT control group were analyzed. Further, using CD36-/- primary hepatocyte culture to verify whether OPG was regulated by CD36 to regulate the liver cells. Finally, the expression of CD36 is regulated by the use of PPAR gamma inhibitor GW9662 and ERK inhibitor SCH772984 to verify whether OPG passes through p-ERK and PPAR gamma regulates the expression of CD36. Results: after OPG-Fc treatment, C57 primary hepatocytes are increased, the expression of fatty acid uptake gene is increased, the expression of fatty acid uptake gene is increased, and the expression of nuclear receptor gene is increased, and the activity of PPAR is reduced. Compared with the WT control group, the intracellular TG decreased, the expression of fatty acid uptake gene CD36 decreased, the PPAR gamma expression of the nuclear receptor gene decreased and the p-ERK activity increased. In the original CD36-/- generation, OPG-Fc could not increase the intracellular TG content. After GW9662, OPG-Fc could not increase the expression of CD36. OPG-Fc can not increase the expression of PPAR gamma and CD36. Conclusion: OPG regulates the triglyceride level of liver by ERK-PPAR -CD36 -CD36 axis.

【學(xué)位授予單位】：重慶醫(yī)科大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2017
【分類號(hào)】：R575.5

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