Regulation of absorption and ABC1-mediated efflux of cholesterol by RXR heterodimers

Several nuclear hormone receptors involved in lipid metabolism form obligate heterodimers with retinoid X receptors (RXRs) and are activated by RXR agonists such as rexinoids. Animals treated with rexinoids exhibited marked changes in cholesterol balance, including inhibition of cholesterol absorption and repressed bile acid synthesis. Studies with receptor-selective agonists revealed that oxysterol receptors (LXRs) and the bile acid receptor (FXR) are the RXR heterodimeric partners that mediate these effects by regulating expression of the reverse cholesterol transporter, ABC1, and the rate-limiting enzyme of bile acid synthesis, CYP7A1, respectively. Thus, these RXR heterodimers serve as key regulators of cholesterol homeostasis by governing reverse cholesterol transport from peripheral tissues, bile acid synthesis in liver, and cholesterol absorption in intestine.     

A natural product that lowers cholesterol as an antagonist ligand for FXR

Extracts of the resin of the guggul tree (Commiphora mukul) lower LDL (low-density lipoprotein) cholesterol levels in humans. The plant sterol guggulsterone [4,17(20)-pregnadiene-3,16-dione] is the active agent in this extract. We show that guggulsterone is a highly efficacious antagonist of the farnesoid X receptor (FXR), a nuclear hormone receptor that is activated by bile acids. Guggulsterone treatment decreases hepatic cholesterol in wild-type mice fed a high-cholesterol diet but is not effective in FXR-null mice. Thus, we propose that inhibition of FXR activation is the basis for the cholesterol-lowering activity of guggulsterone. Other natural products with specific biologic effects may modulate the activity of FXR or other relatively promiscuous nuclear hormone receptors.     

饲喂益生菌Lactobacillus casei Zhang对高脂日粮大鼠肝脏脂质代谢的作用

【目的】研究不同剂量益生菌L. casei Zhang（2.0×1010 CFU/d、2.0×109 CFU/d和2.0×108 CFU/d）及其发酵乳饮料（2.0×108 CFU/mL/d）对高胆固醇血症大鼠肝脏脂质的治疗作用。【方法】采用高脂饲料诱导高脂血症,采用相应试剂盒测定肝脏总胆固醇水平（TC）和甘油三酯（TG）水平、粪便总胆汁酸水平与胆固醇水平以及血清载脂蛋白ApoAⅠ与ApoB水平。【结果】益生菌各剂量组和发酵饮料组与高脂模型组相比,肝脏总胆固醇水平（TC）和甘油三酯（TG）水平均显著降低(P＜0.05 或P＜0.01)。各试验组均可显著增加高血脂大鼠粪便总胆汁酸水平和血清载脂蛋白ApoAⅠ水平以及显著降低血清载脂蛋白ApoB水平(P＜0.01),但对粪便胆固醇水平影响不明显(P＞0.05)。【结论】益生菌L. casei Zhang主要通过增加总胆汁酸的排出和调节载脂蛋白水平来改善高血脂大鼠肝脏脂质水平。     

小鼠肝再生过程中脂质代谢相关通路中基因的表达谱变化

1材料与方法 1．1材料 试验动物：9周龄的雄性C57BIV6小鼠，自由采食和饮水，每天光照12h，黑暗12h。试剂：TRIzol试剂（Invitrogen）；RNeasy Total RNA Mini Kit（Qiagen）；基因芯片Genechip mouse genome 43020（Affymetrix）；17启动子引物序列（Affymetrix）。     

类固醇代谢相关基因在大鼠肝再生中表达模式和作用分析

为在基因转录水平了解类固醇代谢相关基因在大鼠肝再生(Liver regeneration,LR)中作用,文章通过搜集网站资料和查阅相关论文等方法获得了参与上述代谢活动的基因,用基因芯片检测了它们在大鼠再生肝中表达情况,初步证实上述基因中83个基因与肝再生相关.肝再生启动(PH后0.5～4 h)、G0/GI过渡(PH后4...     

小鼠肝再生过程中脂质代谢相关通路中基因的表达谱变化

[目的]研究肝再生过程中肝脏内脂质代谢通路相关基因的表达谱变化。[方法]建立CC l4诱导肝再生小鼠模型,从小鼠肝组织中提取总RNA,通过微阵列基因芯片技术检测在不同肝再生期间脂质代谢通路相关基因的表达变化,并进行具体功能分析。[结果]肝再生过程中,有98个脂质代谢相关基因的表达水平发生了变化,根据这些基因表达的变化趋势可以分为8组。整体上看,基因表达前期表现为抑制,后期表现为上调。其中,脂肪酸的合成通路基因表达以上调为主,分解代谢通路变化并不明显;大多数胆汁酸合成通路基因在4.5天之前表现为抑制,在4.5天和7天时表现为上调。[结论]肝再生过程中,脂质代谢相关通路间的基因表达变化并不一致,这些数据为进一步研究脂质代谢相关通路对肝再生的调控作用提供了明确的基因范围。     

Vitamin D receptor as an intestinal bile acid sensor

The vitamin D receptor (VDR) mediates the effects of the calcemic hormone 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]. We show that VDR also functions as a receptor for the secondary bile acid lithocholic acid (LCA), which is hepatotoxic and a potential enteric carcinogen. VDR is an order of magnitude more sensitive to LCA and its metabolites than are other nuclear receptors. Activation of VDR by LCA or vitamin D induced expression in vivo of CYP3A, a cytochrome P450 enzyme that detoxifies LCA in the liver and intestine. These studies offer a mechanism that may explain the proposed protective effects of vitamin D and its receptor against colon cancer.     

饲料中胆汁酸对红鳍东方鲀脂肪酸组成及抗氧化能力的影响

为研究饲料中添加胆汁酸对红鳍东方鲀脂肪酸组成及抗氧化能力的影响，以鱼油为主要脂肪源，配制五种等氮饲料，以初始体重14g的红鳍东方鲀进行为期56天的投喂养殖实验。设置适宜脂肪含量(8%)的对照组，并在对照组添加0.02%及0.10%的胆汁酸，分别获得低胆汁酸添加组(BA)和高胆汁酸组(HBA)。另设一高脂组(脂肪含量12.5%，HL组)及高脂+0.02%胆汁酸组(HLBA组)。结果表明，添加胆汁酸的处理组肌肉和肝脏MUFA均低于对照组，其中HBA组显著低于对照组(P<0.05)。肌肉中n-6PUFA含量在HLBA和HL组显著低于其他组(P<0.05)。在适宜脂肪含量的三个处理组间，肝脏中的C20:0、C16:1n-7、C18:1n-9、C18:2n-6、C20:4n-6、C18:3n-3、C18:4n-3、C20:5n-3和C22:6n-3都呈现随着胆汁酸添加量增加而降低的趋势。血清超氧化物歧化酶活性和谷胱甘肽过氧化物酶活性都有随着胆汁酸添加而升高的趋势，且在高脂组显著高于对照组(P<0.05)；血清谷胱甘肽还原酶则呈现相反的趋势。肝脏中谷胱甘肽过氧化物酶1的mRNA相对表达量在对照组显著高于其他组，而BA组氧化还原酶1的基因表达量显著高于对照组；在高脂组添加胆汁酸显著升高了过氧化氢酶的基因表达量。综上所述，饲料中胆汁酸的添加降低了饲料及鱼体组织中一系列长链脂肪酸的含量；胆汁酸对血清抗氧化蛋白活性的影响与其对肝脏抗氧化相关基因表达的影响结果不一致。     

胆汁酸对大菱鲆幼鱼生长、脂肪代谢酶及血清生化的影响

在基础饲料中分别添加0、0.03%、0.06%、0.09%及0.12%的胆汁酸,配制5组等氮等能的实验饲料(D1、D2、D3、D4、D5),投喂体质量为26.5 g的大菱鲆(Scophthalmus maximus)幼鱼56 d,研究胆汁酸对其生长、体组成、脂肪代谢酶活力及血清生化的影响。结果显示:(1)实验鱼的增重率、特定生长率、蛋白质效率及脂肪效率呈先升后平稳的趋势,均在D3组达到最高值。(2)胆汁酸显著降低了全鱼粗脂肪及粗灰分含量,提高了粗蛋白含量(P0.05);降低了肌肉粗脂肪含量,提高了粗蛋白及粗灰分含量(P0.05)。(3)脂肪酶及脂蛋白脂酶活力呈先升后平稳的趋势;肝脂酶活力显著升高(P0.05)。(4)胆汁酸降低了血清谷丙转氨酶及谷草转氨酶活力,提高了碱性磷酸酶活力(P0.05);总蛋白及白蛋白的含量随胆汁酸含量的增加而升高(P0.05);甘油三酯、总胆固醇及高低密度脂蛋白胆固醇含量随胆汁酸含量的升高而下降(P0.05)。(5)鳗弧菌感染48 h后,D3、D4及D5组的累积死亡率显著低于D1组。以增重率为评价指标,经折线回归分析,体质量26.5 g的大菱鲆幼鱼饲料中胆汁酸的适宜添加量为0.09%。     

Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury

Hypertrophic scarring and poor intrinsic axon growth capacity constitute major obstacles for spinal cord repair. These processes are tightly regulated by microtubule dynamics. Here, moderate microtubule stabilization decreased scar formation after spinal cord injury in rodents through various cellular mechanisms, including dampening of transforming growth factor-β signaling. It prevented accumulation of chondroitin sulfate proteoglycans and rendered the lesion site permissive for axon regeneration of growth-competent sensory neurons. Microtubule stabilization also promoted growth of central nervous system axons of the Raphe-spinal tract and led to functional improvement. Thus, microtubule stabilization reduces fibrotic scarring and enhances the capacity of axons to grow.     

玉米须总黄酮对四氯化碳诱导大鼠慢性肝损伤的保护作用研究

[目的]研究玉米须总黄酮（Corn Silk total flavonoid,CSTF）对四氯化碳（CCl4）诱导大鼠慢性肝损伤的保护作用。[方法]在建立大鼠慢性肝损伤模型的同时给予CSTF,56d后观察其对大鼠血清中天门冬氨酸氨基转移酶（AST）、丙氨酸氨基转移酶（ALT）和透明质酸（HA）含量及抗氧化作用的影响,并对肝组织形态学变化进行观察。[结果]CSTF能明显降低慢性肝损伤大鼠的中血清AST、ALT和HA水平,并能明显降低血清和肝脏中丙二醛（MDA）含量,升高超氧化物歧化酶（SOD）活性（P〈0.01或P〈0.05）。[结论]CSTF对CCl4所致的大鼠慢性肝损伤具有较好的保护作用,其机制可能与抗脂质过氧化有关。     

甘草总黄酮对高脂条件下罗非鱼肝损伤的保护作用

为了研究甘草总黄酮对高脂饲料造成的罗非鱼(Oreochromis niloticus)脂肪肝损伤是否具有保护作用,随机将180尾健康无伤罗非鱼分成6组,即对照组、高脂饲料模型组和4个不同浓度甘草总黄酮组(0.05、0.10、0.50、1.00 g·kg^-1甘草总黄酮),每组30尾。饲喂90 d后,采集罗非鱼各实验组肝,测定肝匀浆中超氧化物歧化酶(SOD)活性、还原型谷胱甘肽(GSH)活性、丙二醛(MDA)含量、甘油三酯(TG)含量、总胆固醇(TC)含量、总抗氧化能力(T-AOC)水平,Western blotting法检测肝中核转录因子-κB P65(NF-κB P65)和核转录因子-κB C-Rel (NF-κB C-Rel)蛋白表达水平,RT-PCR法测定肝中微粒体甘油三酸酯转移蛋白(MTTP)和载脂蛋白B100(ApoB100)基因表达情况。结果表明:与对照组相比,高脂饲料模型组罗非鱼肝匀浆中TG、TC、MDA含量极显著(P<0.01)升高,GSH活性、SOD活性、T-AOC水平均极显著(P<0.01)降低;MTTP和ApoB100 mRNA表达水平降低(P<0.01或P<0.05);Western blotting结果显示,NF-κB P 65和C-Rel蛋白表达水平升高。饲料中加入甘草总黄酮后,与高脂饲料模型组相比,罗非鱼肝中GSH活性、SOD活性、T-AOC水平不同程度提高,TC、TG、MDA含量和NF-κB P65、C-Rel蛋白表达水平不同程度降低,MTTP和ApoB100的mRNA表达水平升高,以0.50 g·kg^-1甘草总黄酮组效果较好。说明甘草总黄酮对于罗非鱼脂肪肝损伤具有一定的保护作用,可以缓解高脂饲料造成的脂肪肝损伤。     

Cholesterol: vitamin C controls its transformation to bile acids

Cholesterol accumulates in the blood serum and in the liver of guinea pigs with chronic latent vitamin C deficiency. The reason for this is the decreased rate of transformation of cholesterol to bile acids in the liver of animals deficient in vitamin C. A significant direct correlation exists between the vitamin C concentration in the liver and the rate of cholesterol transformation to bile acids.     

Protein modification by amino acid addition is increased in crushed sciatic but not optic nerves

Rat optic and sciatic nerves were crushed, and 10 minutes to 3 days later nerve segments between the crushed site and the cell body were removed and assayed for posttranslational protein modification by amino acid addition. Protein modification was comparable in intact optic and sciatic nerves, but in sciatic nerves increased to 1.6 times control levels 10 minutes after crushing and reached a maximum of ten times control levels by 2 hours. In optic nerves activity was decreased throughout the time course studied. The results indicate that, in a nerve which is capable of regeneration (sciatic), protein modification by the addition of amino acids increases immediately after injury, but a nerve incapable of regeneration (optic) is incapable of activating the modification reaction. These findings may be important in understanding the reasons for the lack of a regenerative response after injury to central mammalian nerves.     

Platelet-derived serotonin mediates liver regeneration

The liver can regenerate its volume after major tissue loss. In a mouse model of liver regeneration, thrombocytopenia, or impaired platelet activity resulted in the failure to initiate cellular proliferation in the liver. Platelets are major carriers of serotonin in the blood. In thrombocytopenic mice, a serotonin agonist reconstituted liver proliferation. The expression of 5-HT2A and 2B subtype serotonin receptors in the liver increased after hepatectomy. Antagonists of 5-HT2A and 2B receptors inhibited liver regeneration. Liver regeneration was also blunted in mice lacking tryptophan hydroxylase 1, which is the rate-limiting enzyme for the synthesis of peripheral serotonin. This failure of regeneration was rescued by reloading serotonin-free platelets with a serotonin precursor molecule. These results suggest that platelet-derived serotonin is involved in the initiation of liver regeneration.     

几种动物胆汁的组分对比及树脂法精制CDCA初探

采用薄层层析法对蟾蜍、兔、鸡、猪及牛胆汁的组分进行了初步分析,结果表明,蟾蜍胆汁中主要是胆酸(CA)和几种不明物质;兔胆汁中主要是去氧胆酸(DCA)和少量的胆酸(CA);鸡胆汁中以鹅去氧胆酸(CDCA)和胆酸(CA)为主;猪胆汁中主要是鹅去氧胆酸(CDCA)、猪去氧胆酸(HDCA)和石胆酸(LCA)为主;牛胆汁中主要是胆酸(CA)、去氧胆酸(DCA)以及少量的鹅去氧胆酸(CDCA).采用紫外扫描皂化胆汁,确定了皂化胆汁的最大吸收波长,并以此为紫外检测波长首次对离子交换树脂法提取CDCA进行了初步研究并得到了高纯度的CDCA精品.     

Lithocholic acid in human-blood serum

Lithocholic acid was present in the serum of three patients with, jaundice and, in smaller amounts, in two healthy adults. This bile acid occurs naturally in human feces but induces cirrhosis of the liver when fed to a wide variety of experimental animals. The finding of lithocholic acid in blood is of interest because of its possible role in injuring human liver.     

视黄酸诱导动物再生研究进展

综述了视黄酸的概念及其衍生物的特征,探讨了视黄酸对脊椎动物再生作用模式和"超再生"的影响,分析了视黄酸对水螅、蚯蚓、扁形动物和节肢动物等无脊椎动物再生能力的影响,并进一步分析了视黄酸对无脊椎动物发育和再生模式的作用。     

Porphyrin-heme pathway: regulation by intermediates in bile acid synthesis

Dihydroxycoprostane and trihydroxycoprostane, intermediates in normal bile acid synthesis in the liver, enhanced the rate of porphyrin synthesis in cultured liver cells by induction of delta-aminolevulinate synthetase, the rate-limiting enzyme for this pathway. Other 5beta-cholestane derivatives and cholest-5-ene derivatives were ineffective. The selectivity of the induction may indicate that the above-mentioned coprostanes have a physiological role in porphyrin synthesis.     

基于“肝脾理论”探讨肠源性内毒素血症致继发性肝损伤

运用中医肝脾理论相关内容剖析肠源性内毒素血症致继发性肝损伤的发生机制及其治疗思路,并从该角度阐述中西医理论内在联系,认为与肠源性内毒素血症致继发性肝损伤相联系,肠道黏膜屏障功能（intestinal barrier function,IBF）、胆汁酸的肠肝循环、肝与肠道免疫功能相互依赖、IBF障碍与肝损伤的恶性循环、改善肠道功能以保护肝脏的治疗理念均是肝脾理论现代生物学基础的具体体现。