【摘要】：研究背景和目的 隨著肥胖發(fā)病率的上升,非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD)現(xiàn)已成為了世界范圍內(nèi)最常見的慢性肝臟疾病之一,其發(fā)病率是其他常見慢性肝病的幾倍,美國等西方國家發(fā)病率尤為高。而近些年來隨著我國生活水平的提高,我國發(fā)病率也處于一個(gè)逐年上升的階段,接近西方國家。NAFLD是在無過量酒精攝入的情況下患者肝細(xì)胞內(nèi)的脂肪沉積,是由一系列疾病組成的一個(gè)疾病譜,包括單純性脂肪肝、非酒精性脂肪性肝炎、脂肪性肝硬化等,被認(rèn)為是代謝綜合征在肝臟的一種表現(xiàn),具有一系列與代謝綜合征相似的表現(xiàn),如胰島素抵抗、血脂異常、高血壓等,但其發(fā)病機(jī)制現(xiàn)在還不十分清楚,目前認(rèn)為胰島素抵抗是其發(fā)病過程中的關(guān)鍵因素。目前,NAFLD尚無臨床證明有效的藥物,唯一有效的治療方法就是及早發(fā)現(xiàn)疾病,通過減肥及生活方式的改變達(dá)到治療的目的,因此提醒我們開發(fā)研制針對(duì)NAFLD有效藥物的必要性及緊迫性。 膽汁酸核受體,又被稱為類法尼酯X受體(Farnesoid X receptor, FXR),屬于核受體超家族的一員,高表達(dá)于肝臟、胃腸道、腎臟和腎上腺等器官,而心臟、脂肪組織則呈低表達(dá)狀態(tài)。最早人們發(fā)現(xiàn)FXR可調(diào)節(jié)膽汁酸的穩(wěn)態(tài),隨著進(jìn)一步的研究,人們發(fā)現(xiàn)FXR還具有多種新的功能,其中最為重要的可能是其對(duì)代謝紊亂疾病包括NAFLD、糖尿病、高血壓等的調(diào)節(jié)作用。FXR可通過多種途徑調(diào)節(jié)]NAFLD的發(fā)生、發(fā)展過程,例如FXR可改善外周組織的胰島素抵抗及通過調(diào)節(jié)肝臟的糖異生和肝糖分解過程控制葡萄糖穩(wěn)態(tài),可通過多種途徑減少血脂水平從而緩解肝臟甘油三酯積聚、氧化應(yīng)激及脂質(zhì)過氧化等,還可以對(duì)抗肝細(xì)胞的炎癥過程及改善肝臟纖維化狀態(tài),而炎癥和纖維化正是非酒精性脂肪性肝炎重要的病理改變。值得注意的是,NAFLD患者肝臟的FXR表達(dá)水平較正常人低,提示FXR的低表達(dá)狀態(tài)可能在NAFLD的發(fā)生發(fā)展中起著某些作用。結(jié)合FXR的以上特點(diǎn),提示激活FXR可能會(huì)成為治療NAFLD的一種理想手段。 白色脂肪組織是成年人身體中最豐富的組織,也是最大的內(nèi)分泌器官,可分泌多種脂肪因子,包括脂聯(lián)素、瘦素、抵抗素等,而各種脂肪因子通過與全身各組織器官發(fā)生聯(lián)系,共同維持人體內(nèi)的代謝平衡。脂肪因子參與調(diào)節(jié)胰島素抵抗、能量代謝及代謝綜合征的發(fā)生過程,也在NAFLD的發(fā)病機(jī)制中發(fā)揮著重要的作用,如脂聯(lián)素是一種具有胰島素增敏作用的脂肪因子,具有抗炎、抗動(dòng)脈粥樣硬化、抗糖尿病等作用,可減緩NAFLD的進(jìn)程;瘦素可能具有維持糖代謝穩(wěn)態(tài)、保護(hù)肝細(xì)胞、減少脂肪肝的作用；而抵抗素則可引起糖代謝紊亂、胰島素抵抗、脂肪肝等。一些研究顯示NAFLD患者脂肪因子受體的表達(dá)也出現(xiàn)了異常,意味著這些受體也可能參與了NAFLD的發(fā)病過程。 Giovanni Rizzo等證實(shí)了FXR的激活可促進(jìn)脂肪細(xì)胞的分化過程,提示激活FXR可能對(duì)脂肪因子及其受體有一定的調(diào)節(jié)作用,但目前為止,較少實(shí)驗(yàn)研究FXR的激活對(duì)脂肪因子及其受體的影響。因此本實(shí)驗(yàn)的目的即證實(shí)FXR的激活是否可通過直接或間接地調(diào)控脂肪因子及其受體的表達(dá),從而達(dá)到減緩NAFLD發(fā)生、發(fā)展的目的。本實(shí)驗(yàn)通過人工合成的高選擇性的FXR動(dòng)劑GW4064來影響脂肪細(xì)胞分化成熟的整個(gè)過程,研究GW4064對(duì)脂肪細(xì)胞的脂肪因子(包括脂聯(lián)素、瘦素、抵抗素)及其對(duì)應(yīng)受體(脂聯(lián)素受體1(adiponectin receptor1,AdipoRl)、脂聯(lián)素受體2(adiponectin receptor2, AdipoR2)和長型瘦素受體(long form leptin receptor, OB-R))的影響,同時(shí),還研究了GW4064對(duì)脂肪因子作用的靶器官肝臟的脂肪因子受體(AdipoR2和OB-Rb)的影響。因此,本實(shí)驗(yàn)擬從分泌脂肪因子的脂肪細(xì)胞及脂肪因子作用的靶細(xì)胞-肝臟細(xì)胞系統(tǒng)地了解FXR的激活是否能直接或間接調(diào)節(jié)脂肪因子及其受體表達(dá)。 方法 1、HepG2細(xì)胞和3T3-L1前脂肪細(xì)胞的培養(yǎng)。用含10%的胎牛血清、100U/ml的青霉素、100μg/ml的鏈霉素的DMEM培養(yǎng)基培養(yǎng)于37℃、5%CO2環(huán)境中。 2、HepG2細(xì)胞和3T3-L1前脂肪細(xì)胞分組。3T3-L1前脂肪細(xì)胞分組：GW4064組于分化第0天加入5μmol/L GW4064至分化第8天,對(duì)照組則加入等體積的DMSO(因GW4064是用DMSO溶解的),分別取分化第0、2、4、6、8天的細(xì)胞組織和上清液檢測。HepG2細(xì)胞分組：GW4064組加入5μmol/LGW4064,對(duì)照組則加入等體積的DMSO,分別取刺激第0、12、24、48小時(shí)的細(xì)胞組織和上清液檢測。 3、3T3-L1前脂肪細(xì)胞誘導(dǎo)分化為成熟的脂肪細(xì)胞。待細(xì)胞匯合至100%后,繼續(xù)培養(yǎng)2天,此時(shí)細(xì)胞退出生長周期,開始加入分化誘導(dǎo)液Ⅰ(含有0.5mmol/L1-甲基-3-異丁基黃嘌呤(1-methyl-3-isobutyl-xanthin,IBMX),1μmol/L地塞米松,5μg/mL胰島素的完全培養(yǎng)基,此即為分化第0天,記為DO)。分化誘導(dǎo)液Ⅰ處理48小時(shí)(即分化第2天,記為D2)后,換成分化誘導(dǎo)液Ⅱ(含5μg/ml胰島素的完全培養(yǎng)液),分化誘導(dǎo)液Ⅱ處理48小時(shí)(即分化第4天,記為D4)后,換成正常的完全培養(yǎng)基,每2天換一次液,待分化至第8天(記為D8),進(jìn)行油紅O染色,拍照。 4、實(shí)時(shí)熒光定量PCR反應(yīng)(Quantitative Real time PCR,QRT-PCR)檢測3T3-L1前脂肪細(xì)胞分化過程中PPAR-γ2.脂肪因子(脂聯(lián)素、瘦素、抵抗素)及其受體(AdipoR1、AdipoR2、OB-Rb)mRNA的表達(dá)情況及GW4064對(duì)上述基因的影響；檢測GW4064對(duì)HepG2細(xì)胞中脂肪因子受體(AdipoR2、OB-Rb) mRNA表達(dá)的影響。按照說明書,進(jìn)行總RNA的提取、RNA定量和純度檢測、逆轉(zhuǎn)錄合成cDNA和PCR反應(yīng)。擴(kuò)增后得到相關(guān)數(shù)據(jù)和曲線,按相對(duì)定量2-△△Ct法分析得出結(jié)果。 5、酶聯(lián)免疫吸附法(Enzyme linked immunosorbent assay,ELISA)檢測3T3-L1前脂肪細(xì)胞分化過程中上清液中脂肪因子(脂聯(lián)素、抵抗素和瘦素)的含量及GW4064對(duì)其影響：嚴(yán)格按照ELISA試劑盒說明書步驟操作,用酶標(biāo)儀在450nm波長下測定吸光度(OD)值,得出標(biāo)準(zhǔn)曲線,計(jì)算樣品濃度。 6、免疫蛋白質(zhì)印跡(Western blot)檢測3T3-L1前脂肪細(xì)胞分化過程中PPAR-γ2和脂肪因子受體(AdipoRl、AdipoR2和OB-Rb)的蛋白表達(dá)情況及GW4064對(duì)其表達(dá)的影響；檢測GW4064對(duì)HepG2細(xì)胞中脂肪因子受體(AdipoR2和OB-Rb)表達(dá)的影響。步驟包括細(xì)胞總蛋白的提取、測定蛋白濃度、電泳、轉(zhuǎn)膜、免疫反應(yīng)、曝光顯影。 7、數(shù)據(jù)統(tǒng)計(jì)。數(shù)據(jù)統(tǒng)計(jì)分析采用SPSS13.0軟件,所有計(jì)量資料均表示為均數(shù)±標(biāo)準(zhǔn)差(x±s)。兩組樣本間比較采用兩樣本的t檢驗(yàn)；多組樣本間比較需先進(jìn)行方差齊性檢驗(yàn),方差齊,采用單因素方差分析(one-way ANOVA);方差不齊,則采用校正的F檢驗(yàn)(Welch法)。P0.05被認(rèn)為差異具有統(tǒng)計(jì)學(xué)意義。所有實(shí)驗(yàn)均重復(fù)3次。 結(jié)果 1.3T3-L1前脂肪細(xì)胞的分化成熟。經(jīng)過分化誘導(dǎo)液Ⅰ、Ⅱ的作用,3T3-L1前脂肪細(xì)胞在分化第2天即可見到細(xì)胞由梭形向圓形變化,分化第4天可見細(xì)胞變圓的同時(shí)細(xì)胞內(nèi)有脂滴形成,分化第8天可見到75%-85%細(xì)胞變圓、內(nèi)含大量脂滴、油紅O染為紅色,即為分化成熟的脂肪細(xì)胞。 2. QRT-PCR檢測3T3-L1前脂肪細(xì)胞分化過程中PPAR-γ2、脂肪因子(脂聯(lián)素、瘦素、抵抗素)及其受體(AdipoR1、AdipoR2、OB-Rb)mRNA的表達(dá)情況及GW4064對(duì)上述基因的影響。在3T3-L1前脂肪細(xì)胞未分化時(shí),瘦素、抵抗素、PPAR-γ2及脂肪因子受體(AdipoR1、AdipoR2和OB-Rb)mRNA即可被檢測到,而脂聯(lián)素在分化第4天才可被檢測到,并且上述基因均隨著脂肪細(xì)胞的分化成熟表達(dá)量逐漸增加,其中脂聯(lián)素、瘦素、AdipoR2、PPAR-γ2在經(jīng)過GW4064刺激后表達(dá)量較對(duì)照組明顯升高,差異具有統(tǒng)計(jì)學(xué)意義(P0.05)。 3. QRT-PCR檢測GW4064對(duì)HepG2細(xì)胞中脂肪因子受體(AdipoR2和OB-Rb)mRNA的表達(dá)的影響。GW4064刺激后AdipoR2、OB-Rb mRNA相對(duì)表達(dá)量呈時(shí)間依賴性的增加,差異具有統(tǒng)計(jì)學(xué)意義(P0.05)。 4.ELISA檢測脂肪因子(脂聯(lián)素、瘦素和抵抗素)在3T3-L1前脂肪細(xì)胞分化過程中蛋白的表達(dá)情況及GW4064對(duì)其表達(dá)的影響。脂聯(lián)素、瘦素、抵抗素均隨著細(xì)胞的分化成熟蛋白表達(dá)量逐漸增加,且經(jīng)過GW4064刺激后,脂聯(lián)素、瘦素表達(dá)量顯著高于對(duì)照組(P0.05),而抵抗素則無明顯改變。 5.Western blot檢測3T3-L1前脂肪細(xì)胞分化過程中PPARγ2及脂肪因子受體(AdipoR1、AdipoR2和OB-Rb)的蛋白表達(dá)情況及GW4064對(duì)其表達(dá)的影響。PPARγ2、AdipoR1、AdipoR2和OB-Rb均隨著3T3-L1前脂肪細(xì)胞的分化成熟表達(dá)量逐漸增加,其中,GW4064刺激后PPARγ2的蛋白表達(dá)顯著高于對(duì)照組(P0.05),而AdipoR1、AdipoR2和OB-Rb則無明顯改變。 6.Western blot檢測GW4064對(duì)HepG2細(xì)胞中脂肪因子受體(AdipoR2和OB-Rb)蛋白表達(dá)情況的影響。在HepG2細(xì)胞中,AdipoR2在經(jīng)過GW4064刺激后蛋白表達(dá)量呈時(shí)間依賴性的增加(P0.05)；而OB-Rb則無明顯改變。 結(jié)論 本研究證實(shí)FXR激動(dòng)劑GW4064刺激3T3-L1前脂肪細(xì)胞可以上調(diào)其PPAR-γ2、脂聯(lián)素、瘦素及AdipoR2mRNA的表達(dá),同時(shí)可以促進(jìn)PPAR-γ2、脂聯(lián)素、瘦素蛋白的表達(dá)；另外,GW4064刺激HepG2細(xì)胞可上調(diào)其AdipoR2及OB-Rb mRNA的表達(dá),并促進(jìn)AdipoR2蛋白的表達(dá)。上述結(jié)果表明,FXR激動(dòng)劑可影響脂肪細(xì)胞中某些脂肪因子及其受體的表達(dá),亦可影響肝細(xì)胞的某些脂肪因子受體的表達(dá)。我們的實(shí)驗(yàn)結(jié)果還提示FXR激動(dòng)劑對(duì)脂肪因子及其相關(guān)受體的影響可能通過或者部分通過誘導(dǎo)PPAR-γ的表達(dá)而實(shí)現(xiàn)的,后者可調(diào)節(jié)脂肪細(xì)胞分化過程中多種基因的表達(dá)。因脂肪因子及其受體在NAFLD的發(fā)生、發(fā)展中發(fā)揮著關(guān)鍵作用,提示FXR激動(dòng)劑對(duì)NAFLD的作用可能是通過影響脂肪因子及其受體而實(shí)現(xiàn)的,這為進(jìn)一步了解FXR對(duì)NAFLD的作用機(jī)制及其成為NAFLD的有效藥物的可能性提供了理論基礎(chǔ)。
[Abstract]:Research background and purpose
With the increasing incidence of obesity, non-alcoholic fatty liver disease (NAFLD) has become one of the most common chronic liver diseases in the world. The incidence of NAFLD is several times that of other common chronic liver diseases, especially in the United States and other Western countries. NAFLD is a fatty deposit in the hepatocytes of patients without excessive alcohol intake. It is a spectrum of diseases, including simple fatty liver disease, non-alcoholic fatty liver disease, fatty liver cirrhosis and so on. It is considered to be metabolic synthesis. One of the manifestations of hepatic syndrome has a series of similar manifestations with metabolic syndrome, such as insulin resistance, dyslipidemia, hypertension, etc. However, the pathogenesis is still unclear. Insulin resistance is considered to be the key factor in the pathogenesis of hepatic syndrome. The method is to discover the disease as early as possible and achieve the goal of treatment through weight loss and lifestyle changes. Therefore, it reminds us of the necessity and urgency of developing effective drugs for NAFLD.
Bile acid receptors, also known as Farnesoid X receptors (FXR), are a member of the nuclear receptor superfamily. They are highly expressed in the liver, gastrointestinal tract, kidneys and adrenal glands, while low-expression in the heart and adipose tissue. FXR also has a variety of new functions, the most important of which may be its regulatory role in metabolic disorders including NAFLD, diabetes, hypertension and so on. Glucose homeostasis can alleviate triglyceride accumulation, oxidative stress and lipid peroxidation in the liver by reducing blood lipid levels in various ways. It can also resist inflammation of hepatocytes and improve liver fibrosis. Inflammation and fibrosis are important pathological changes in NAFLD. The expression of FXR in the liver of the patients was lower than that of the normal subjects, suggesting that the low expression of FXR may play a role in the development of NAFLD.
White adipose tissue is the most abundant tissue and the largest endocrine organ in adults. It secretes many kinds of adipocytokines, including adiponectin, leptin, resistin and so on. All kinds of adipocytokines maintain the metabolic balance of the human body by contacting with various tissues and organs of the whole body. Adiponectin is an insulin-sensitized adipokine with anti-inflammatory, anti-atherosclerosis, anti-diabetes and other effects, which can slow down the process of NAFLD; leptin may maintain glucose metabolism homeostasis and protect liver cells. Some studies have shown abnormal expression of adipokine receptors in NAFLD patients, suggesting that these receptors may also be involved in the pathogenesis of NAFLD.
Giovanni Rizzo et al confirmed that activation of FXR can promote the differentiation of adipocytes, suggesting that activation of FXR may regulate adipocytokines and their receptors to some extent, but so far, few experiments have studied the effect of FXR activation on adipocytokines and their receptors. In this study, we investigated the effects of GW4064 on adipocyte adipokines (including adiponectin, leptin, resistin) and their corresponding receptors in adipocytes by affecting the whole process of adipocyte differentiation and maturation by synthesizing highly selective FXR agonist GW4064. The effects of GW4064 on adiponectin receptor 1 (AdipoRl), adiponectin receptor 2 (AdipoR2) and long form leptin receptor (OB-R) were also studied. The effects of GW4064 on adiponectin receptor 2 (AdipoR2) and OB-Rb (long form leptin receptor, OB-R) in the liver, the target organs of adipokines, were also studied. Adipocytes secreting adipokines and hepatocytes, the targets of adipokines, systematically understand whether FXR activation directly or indirectly regulates the expression of adipokines and their receptors.
Method
1, HepG2 cells and 3T3-L1 preadipocytes were cultured in DMEM medium containing 10% fetal bovine serum, 100U/ml penicillin and 100ug/ml streptomycin at 37 C and 5% CO2.
2. HepG2 cells and 3T3-L1 preadipocytes. 3T3-L1 preadipocyte group: GW4064 group was added 5 micromol/L GW4064 on the 0th day of differentiation to the 8th day of differentiation, while the control group was added DMSO of equal volume (because GW4064 was dissolved in DMSO). Cell tissues and supernatant of the 0th, 2nd, 4th, 6th and 8th day of differentiation were obtained and detected respectively. Cell tissues and supernatants were obtained at 0, 12, 24 and 48 hours of stimulation respectively.
3,3T3-L1 preadipocytes were induced to differentiate into mature adipocytes. After confluence to 100%, the cells were cultured for 2 days. At this time, the cells withdrew from the growth cycle and began to add differentiation inducing medium I (containing 0.5mmol/L 1-methyl-3-isobutyl-xanthin, IBMX), 1 micromol/L dexamethasone, 5 microgram/ml insulin) into the complete medium. Differentiation induction fluid I was treated for 48 hours (i.e. the second day of differentiation, denoted as D2), then changed into differentiation induction fluid II (complete medium containing 5 ug/ml insulin), treated for 48 hours (i.e. the fourth day of differentiation, denoted as D4), and changed into normal complete medium every 2 days until the eighth day (record) For D8), oil red O was stained and photographed.
4. Quantitative Real-time PCR (QRT-PCR) was used to detect the expression of PPAR-gamma 2. Adiponectin (adiponectin, leptin, resistin) and its receptor (AdipoR1, AdipoR2, OB-Rb) mRNA during the differentiation of 3T3-L1 preadipocytes, and the effect of GW4064 on the expression of Adipo receptor (Adipo receptor) in HepG2 cells. R2, OB-Rb) mRNA expression. According to the instructions, total RNA extraction, RNA quantitative and purity detection, reverse transcription synthesis of cDNA and PCR reaction. After amplification, the relevant data and curves were obtained, according to the relative quantitative 2-delta CT analysis results.
5. Enzyme linked immunosorbent assay (ELISA) was used to detect the adiponectin (adiponectin, resistin and leptin) content in the supernatant of 3T3-L1 preadipocyte during differentiation and the effect of GW4064 on it. The absorbance (OD) value was determined by enzyme-linked immunosorbent assay (ELISA) at 450 nm. The standard curve is used to calculate the sample concentration.
6. Western blot was used to detect the expression of PPAR-gamma 2 and adipokine receptors (AdipoRl, AdipoR2 and OB-Rb) during the differentiation of 3T3-L1 preadipocytes and the effect of GW4064 on the expression of adipokine receptors (AdipoR2 and OB-Rb) in HepG2 cells. Extraction, determination of protein concentration, electrophoresis, transfer membrane, immune reaction, exposure development.
7. Data statistics. SPSS13.0 software was used for statistical analysis of data. All measurement data were expressed as mean (+ standard deviation) (x (+ s). The comparison between two groups of samples was conducted by t test of two samples; the comparison between multiple groups of samples was conducted by homogeneity test of variance, homogeneity of variance, one-way ANOVA; and the variance was not homogeneous, F test was used for correction. The Welch (.P0.05) method was considered to be statistically significant. All experiments were repeated 3 times.
Result
1.3T3-L1 preadipocytes differentiated and matured. After the effect of differentiation inducer I and II, 3T3-L1 preadipocytes changed from spindle to round on the 2nd day of differentiation. On the 4th day of differentiation, fat droplets formed in the cells while the cells became round. On the 8th day of differentiation, 75% - 85% of the cells became round, containing a large number of lipid droplets and oil red O stained red. Color is the differentiation of mature adipocytes.
2. QRT-PCR was used to detect the expression of PPAR-gamma 2, adiponectin (adiponectin, leptin, resistin) and its receptor (AdipoR1, AdipoR2, OB-Rb) mRNA during the differentiation of 3T3-L1 preadipocytes and the effect of GW4064 on the above genes. NA could be detected immediately, and adiponectin could be detected only on the 4th day of differentiation, and the expression of the above genes increased gradually with the differentiation and maturation of adipocytes. The expression of adiponectin, leptin, AdipoR2 and PPAR-gamma-2 increased significantly after GW4064 stimulation compared with the control group (P 0.05).
3. The effect of GW4064 on the expression of adipokine receptor (AdipoR2 and OB-Rb) mRNA in HepG2 cells was detected by QRT-PCR. The relative expression of AdipoR2 and OB-Rb mRNA increased in a time-dependent manner after GW4064 stimulation, and the difference was statistically significant (P 0.05).
4. ELISA was used to detect the expression of adiponectin (adiponectin, leptin and resistin) during the differentiation of 3T3-L1 preadipocytes and the effect of GW4064 on the expression of adiponectin, leptin and resistin. Group (P0.05), but resistin did not change significantly.
5. Western blot was used to detect the expression of PPAR-gamma-2 and adipokine receptors (AdipoR1, AdipoR2 and OB-Rb) during the differentiation of 3T3-L1 preadipocytes and the effect of GW4064 on the expression of PPAR-gamma-2, AdipoR1, AdipoR2 and OB-Rb. The expression was significantly higher than that in the control group (P0.05), while AdipoR1, AdipoR2 and OB-Rb did not change significantly.
6. Western blot was used to detect the effect of GW4064 on the expression of adipokine receptors (AdipoR2 and OB-Rb) in HepG2 cells.
conclusion
This study confirmed that FXR agonist GW4064 stimulated 3T3-L1 preadipocytes to up-regulate the expression of PPAR-gamma-2, adiponectin, leptin and AdipoR2 mRNA, and to up-regulate the expression of PPAR-gamma-2, adiponectin and leptin. In addition, GW4064 stimulated HepG2 cells to up-regulate the expression of AdipoR2 and OB-Rb mRNA, and promoted the expression of AdipoR2 protein. Our results also suggest that FXR agonists may affect the expression of some adipocytokines and their receptors in adipocytes and some adipocytokine receptors in hepatocytes. Our results also suggest that the effects of FXR agonists on adipocytokines and their receptors may be mediated by or in part by inducing the expression of PPAR-gamma, the latter. Fatty factor and its receptor play a key role in the development of NAFLD, suggesting that the effect of FXR agonists on NAFLD may be achieved by affecting the expression of Adipocyte Factor and its receptor. This will help us to understand the mechanism of FXR on NAFLD and its role in NAFLD. The possibility of effective drugs provides a theoretical basis.
【學(xué)位授予單位】：南方醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2014
【分類號(hào)】：R575.5

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本文編號(hào)：2239104