肝X受体在胆固醇代谢过程中的作用机制

胆固醇是细胞膜的组成成分,对维持机体代谢及正常的功能有着至关重要的作用。肝X受体(LXR)是肝脏中丰富表达的一种核受体,通过在肝细胞层面调控胆固醇及胆汁酸的合成、转化及转运来影响胆固醇代谢过程,在维持机体胆固醇稳态中发挥重要作用。另外,LXR能抑制食物中胆固醇在肠道的吸收,从而降低机体外源性胆固醇水平,从一定程度上降低机体总胆固醇水平,预防高胆固醇血症、胆结石等的形成。从肝脏和肠道两个层面对LXR调控胆固醇代谢的机制进行了总结。     

胆汁酸代谢途径的研究进展

肝脏的胆汁酸代谢在维持机体的胆固醇稳态中起了重要的作用。本文对胆汁酸代谢的两条途径和它们在整个胆汁酸代谢中的相应地位及与胆汁酸代谢紊乱相关的两种疾病作一综述。     

胆汁酸代谢途径的研究进展

肝脏的胆汁酸代谢在维持机体的胆固醇稳态中起了重要的作用。本对胆汁酸代谢的两条途径和它们在整个胆汁酸代谢中的相应地位及与胆汁酸代谢紊乱相关的两种疾病作一综述。     

胆汁酸代谢与调控研究进展

胆汁酸是胆汁的主要成分,在肝细胞内由胆固醇转化而来,是肝脏清除胆固醇的主要方式。胆汁酸可促进脂类的消化和吸收,抑制胆汁中胆固醇的析出。胆汁酸的代谢包括合成、摄取转运、加工、排泄和肠肝循环等过程。上述过程的有序进行是保证体内胆汁酸正常代谢和机体稳态的基础,而体内对胆汁酸各个代谢过程的精细调控则是基础的保障。此文主要针对胆汁酸代谢调控进展,从分子和基因水平作一综述。     

靶向肝X受体的抗动脉粥样硬化药物研究进展

肝X受体(LXR)是机体胆固醇稳态维持的重要调控因子,通过调控下游靶基因表达,参与调节各组织中的胆固醇代谢。LXR激动剂能够促进胆固醇逆向转运,发挥抗动脉粥样硬化作用,具有潜在治疗心血管疾病的作用。本文围绕近年来新型LXR激动剂,从不同来源、特点和作用机制等角度对其发挥抗动脉粥样硬化作用进行综述。     

结核分枝杆菌感染对巨噬细胞内胆固醇代谢影响的机制的研究进展

正常情况下,胆固醇在巨噬细胞内的代谢过程主要包括胆固醇的摄取、酯化、水解以及外排,在机体严谨精细的调控下正常进行,维持巨噬细胞内脂质的动态平衡。胆固醇代谢稳态是维持细胞正常形态和功能的重要环节之一,如果过程中出现异常,发生代谢紊乱,就会破坏和改变细胞的结构。结核分枝杆菌感染宿主巨噬细胞之后,与宿主巨噬细胞的相互作用会影响着结核分枝杆菌的最终状态,其中胆固醇代谢在这一过程中发挥了重要作用。本文以胆固醇为线索,将结核分枝杆菌感染巨噬细胞后对胆固醇代谢影响的机制作一综述。     

他汀类药物的肝脏安全性

他汀类药物通过抑制肝脏胆固醇合成,降低总胆固醇尤其是低密度脂蛋白胆固醇(LDL-C).脂溶性他汀主要通过肝脏细胞色素P450酶系代谢后经肝脏清除.因此,肝脏是他汀类药物发挥药理作用以及代谢和排泄的主要器官.     

淋巴管参与胆固醇逆向转运

细胞需要胆固醇才能生存,但过量的胆固醇对细胞具有毒性,因此细胞需要调节胆固醇的稳态。细胞内胆固醇被转运到高密度脂蛋白载脂蛋白AI,会以胆固醇逆向转运的方式返回肝脏代谢。胆固醇逆向转运不仅是维持细胞胆固醇稳态所需的生理过程,而且对动脉粥样硬化发展起到潜在的抑制作用。目前的研究主要集中在细胞胆固醇流出的最初途径和最终代谢上,但关于胆固醇是如何离开血液却知之甚少。越来越多的研究表明,在胆固醇逆向转运过程中高密度脂蛋白需要通过淋巴管转运以返回到肝脏代谢。因此,研究高密度脂蛋白从血液流入外周组织的过程,以及它是怎样通过淋巴管转运对治疗动脉粥样硬化具有重要意义。本综述主要介绍淋巴管与胆固醇逆向转运之间的联系,为治疗动脉粥样硬化性心血管疾病提供新的策略。     

维持体内胆固醇稳态的重要膜蛋白

正胆固醇是人体中必不可少的物质,体内胆固醇含量过高会引起动脉粥样硬化性心血管疾病及脂质代谢异常相关疾病,含量过低可引起血管脆性增加、激素缺乏、免疫力下降及癌症发病率增高等病理过程,因此,维持体内胆固醇稳态对人体健康至关重要~([1])。人体内胆固醇代谢受多方面的调节,包括自身合成、小肠吸收、胆汁分泌、粪便排泄,其中一些膜蛋白在过程中发挥重要作用。1维持消化道胆固醇稳态的重要膜蛋白体内胆固醇主要是通过肝脏合成和肠道吸收两种途径     

慢性肝病的脂质代谢和外源脂质的补充

各种病因所致的肝脏损害及肝脏疾病的各临床阶段均可伴有营养不良，发生率高达90％左右”’。它严重影响肝脏再生能力和肝功能恢复，不利患者生存“，“。营养支持治疗可以有效地改善患者营养状态以利疾病恢复。肝病患者外源脂质的补充一直存在争议。现就有关问题作一简单综述。一、慢性肝病时的脂质代谢肝脏是脂质代谢的枢纽器官。脂肪酸、胆固醇、磷脂和载脂蛋白均在肝脏合成。脂蛋白代谢也在肝脏进行“’。慢性肝病时常有血脂和脂蛋白异常。载脂蛋白和脂蛋白分解所需的各种酶的合成均减少；载脂蛋白与脂质的结合受干扰，故高密度脂蛋白、…     

脂蛋白血管外循环与胆固醇逆向转运

胆固醇逆向转运是机体周围组织细胞胆固醇转运至肝脏转化排泄的重要生理过程，它在维持机体胆固醇平衡和防止动脉粥样硬化的发生和发展过程中起着重要的作用。脂蛋白是胆固醇的载体，血浆脂蛋白可以透过血管壁进入间质组织，通过与组织细胞直接接触接受细胞释出的胆固醇，再经淋巴液或直接返回血浆，并运至肝脏代谢。因此，脂蛋白血管外循环是胆固醇逆向转运重要组成部分。研究脂蛋白血管外循环的过程、特征以及代谢变化的规律，对心血管病的防治具有重要的理论和实践价值。     

依折麦布长期干预对LDLR＋/－仓鼠高脂血症的影响及其对肝脏脂代谢基因的调控

目的探讨依折麦布长期干预调控脂代谢的效果和对肝脏脂代谢基因的调控。方法雄性低密度脂蛋白受体杂合子(LDLR^+/-)仓鼠随机分为两组:空白对照组和依折麦布组[25 mg/(kg·d)]。动物高脂饮食同时给药20周后,收集血浆、肝脏等组织样本。分析血浆中总胆固醇(TC)、甘油三酯(TG)、总胆汁酸(TBA)、非酯化脂肪酸(NEFA)和谷草转氨酶(AST)水平;检测肝脏中TC和TG水平;借助KTA快速蛋白液相色谱系统分离脂蛋白组分并检测各组分的TC和TG水平;采用实时荧光定量PCR和Western blot分别检测脂代谢相关基因和蛋白的表达。结果依折麦布长期干预显著下调LDLR^+/-仓鼠血浆中的TC、TG、TBA、NEFA和AST水平以及载脂蛋白B(ApoB)蛋白表达水平,但对脂蛋白脂肪酶(LPL)的蛋白表达和活性以及前蛋白转化酶枯草溶菌素9(PCSK9)的蛋白水平无影响;在肝脏中,依折麦布显著降低了TC水平,但对TG无显著影响;在基因水平上,依折麦布显著上调肝脏中甾醇调节元件结合蛋白2(SREBP-2)和PCSK9的表达,同时下调了胆固醇7α羟化酶A1(CYP7A1)、三磷酸腺苷结合盒转运体G5(ABCG5)、ABCG8和肝X受体α(LXRα)的表达。结论在LDLR^+/-仓鼠中,依折麦布长期干预可显著降低高脂血症,并展现出对多种肝脏脂代谢相关基因表达调控的复杂性。     

Emerging roles of the intestine in control of cholesterol metabolism

INTRODUCTIONMaintenance of cholesterol homeostasis in the body requires accurate metabolic cross-talk between processes that govern de novo cholesterol synthesis and turnover to adequately cope with(large)fluctuations in dietary cholesterol intake.Imbalance may lead to elevated plasma cholesterol levels and increased risk for cardiovascular diseases(CVD),the main cause of death in Western society.A multitude of epidemiological studies has shown the direct link between high plasma cholest…     

Emerging roles of the intestine in control of cholesterol metabolism

The liver is considered the major "control center" for maintenance of whole body cholesterol homeostasis. This organ is the main site for de novo cholesterol synthesis,clears cholesterol-containing chylomicron remnants and low density lipoprotein particles from plasma and is the major contributor to high density lipoprotein (HDL; good cholesterol) formation. The liver has a central position in the classical definition of the reverse cholesterol transport pathway by taking up peripheryderived cholesterol from lipoprotein particles followed by conversion into bile acids or its direct secretion into bile for eventual removal via the feces. During the past couple of years, however, an additional important role of the intestine in maintenance of cholesterol homeostasis and regulation of plasma cholesterol levels has become apparent. Firstly, molecular mechanisms of cholesterol absorption have been elucidated and novel pharmacological compounds have been identified that interfere with the process and positively impact plasma cholesterol levels. Secondly, it is now evident that the intestine itself contributes to fecal neutral sterol loss as a cholesterol-secreting organ. Finally, very recent work has unequivocally demonstrated that the intestine contributes significantly to plasma HDL cholesterol levels.Thus, the intestine is a potential target for novel antiatherosclerotic treatment strategies that, in addition to interference with cholesterol absorption, modulate direct cholesterol excretion and plasma HDL cholesterol levels.     

Acyl-coenzyme A:Cholesterol acyltransferase in human liver. In vitro detection and some characteristics of the enzyme

The enzyme, acyl-coenzyme A:cholesterol acyltransferase (ACAT), is responsible for the intracellular esterification of cholesterol. Although it has been detected in the liver from a variety of animals and in human skin fibroblasts and human intestine, it has been reported to be absent from human liver. Since this enzyme may play an important role in cholesterol homeostasis, evidence for its presence in human liver was again sought. Using labeled oleoyl CoA and the endogenous cholesterol as reactants, ACAt was detected in fresh samples of human liver obtained from patients undergoing staging laparotomy for Hodgkin's disease. The enzyme is present almost exclusively in membrane fractions with little activity detected in cytosol. Microsomal ACAt activity was linear with incubation time for up to 10 min. After this, the rate of cholesterol esterification remained constant despite the fact that adequate acyl CoA was present as judged by the continued incorporation of oleate into triglyceride. ACAT activity is destroyed by heating at 100°C for 10 min. It was inhibited only up to 20%–30% by 1 mM 5,5′-dithiobis-(2-nitrobenzoic acid), which completely inactivates the serum cholesterol esterifying enzyme, lecithin:cholesterol acyltranferase (LCAT). Like ACAT in human skin fibroblasts, human liver ACAT was also inhibited by progesterone in vitro. ACAT activity averaged 10.3 ± 5.1 pmole cholesteryl oleate/min/mg microsomal protein for 3 normal livers and 39.0 ± 12.5 for 2 fatty livers. Thus, the level of ACAT activity estimated for the whole liver was 2.1–35.8 μmole/hr in the fasting state. This activity may account for some portion of the cholesterol esters present in plasma VLDL in fasting normolipidemic individuals. However, it is likely that the major role of hepatic ACAT is in the regulation and maintenance of hepatic cholesterol homeostasis.     

Effect of probucol in lecithin-cholesterol acyltransferase-deficient mice: inhibition of 2 independent cellular cholesterol-releasing pathways in vivo

Cellular cholesterol release takes place by at least 2 distinct mechanisms: the lecithin-cholesterol acyltransferase (LCAT)-driven net efflux by cholesterol diffusion and the generation of high density lipoprotein (HDL) with cellular cholesterol and phospholipid on the cell-apolipoprotein interaction. Therefore, LCAT deficiency impairs the former pathway, and the latter can be inhibited by probucol, which interferes with the apolipoprotein-cell interaction. Hence, probucol was given to the LCAT-deficient mice in the attempt to suppress both of these pathways. The mice were fed low (0.2%) and high (1.2%) cholesterol diets containing 0.5% probucol for 2 weeks. LCAT deficiency and probucol markedly decreased plasma HDL, and the effects were synergistic. Tissue cholesterol content was lower in the adrenal glands and ovaries in the LCAT-deficient mice and in the probucol-treated mice, suggesting that HDL is a main cholesterol provider for these organs. It was also moderately decreased in the spleen of the low cholesterol-fed female mice and in the thyroid gland of the low cholesterol-fed male mice. On the other hand, the esterified cholesterol content in the liver was substantially increased by the probucol treatment with a high cholesterol diet in the LCAT-deficient mice but not in the wild-type mice. Among the groups, there was no significant difference in the tissue cholesterol levels in other organs, such as the liver, spleen, thymus, brain, erythrocytes, thyroid gland, testis, and aorta, resulting from either LCAT deficiency or probucol. Thus, the apolipoprotein-mediated mechanism plays a significant role in the export of cellular cholesterol in the liver, indicating that the liver is a major site of the HDL assembly. Otherwise, tissue cholesterol homeostasis can largely be maintained in mice even when the assembly of new HDL is inhibited by probucol in the absence of LCAT. Nonspecific diffusion of cholesterol perhaps adequately maintains the homeostasis in the experimental condition.