固醇调节元件结合蛋白与脂质代谢

固醇调节元件结合蛋白(sterol regulatory element-binding proteins,SREBPs)是脊椎动物细胞脂质稳态的转录调节物,可直接激活多个参与胆固醇、脂肪酸、甘油三酯、磷脂合成和摄取,以及辅助因子NADPH等基因的表达,从而调控胆固醇及脂肪酸等脂类的代谢过程。本文综述了SREBPs转运和活化的过程,以及调节细胞脂质稳态功能的分子机制,并探讨了其在脂代谢紊乱相关疾病发生中的重要作用。     

脑铁代谢及调控

随着研究的深入,脑铁代谢相关分子突变引起的疾病越来越多的被人们所认识。脑铁代谢紊乱可能是神经退行性疾病的发病原因之一。对脑铁代谢机理的认识将为预防和治疗脑铁代谢紊乱相关疾病提供重要的理论根据。对脑铁代谢的过程,脑铁代谢的相关分子以及这些分子对脑内铁稳态的调控作用作一介绍。     

PI3K-Akt信号转导通路对脂代谢的调控作用

脂代谢紊乱与多种疾病的发生发展有关,严重威胁着公共健康。近年来,关于PI3K-Akt信号通路在2型糖尿病、肥胖、肿瘤代谢与免疫及心脑血管疾病等方面的研究层出不穷,本文旨在综述PI3K-Akt信号通路与多个脂代谢相关基因、多个脂代谢器官以及多种脂代谢紊乱相关疾病之间的重要联系,探讨其直接/间接参与脂质合成、转运、摄入与分解过程的分子机制及病理状态下的信号转导调控,以期为脂代谢紊乱相关疾病的治疗提供新的参考靶点。     

N6-腺苷酸甲基化修饰在脂质代谢紊乱疾病中调控作用研究进展

脂质代谢是一个复杂的生理过程,与营养调节、激素平衡和内分泌作用密切相关,它涉及多种因子和信号转导通路的互作。脂质代谢紊乱是诱发多种疾病的主要机制之一,如肥胖症、糖尿病、非酒精性脂肪肝病、肝炎、肝细胞癌及其并发症等。目前越来越多的研究发现RNA上发生的N⁶-腺苷酸甲基化(N⁶-adenylate methylation, m⁶A)“动态修饰”代表了一种全新的“转录后”调控方式,mRNA、tRNA、ncRNA等均可发生m⁶A修饰,m⁶A修饰异常调控基因表达变化和可变剪切事件发生。据最新文献报道,m⁶ARNA修饰参与了脂质代谢紊乱的表观遗传学调控。本文基于脂质代谢紊乱诱发的主要疾病,综述m⁶A修饰在其发生和发展中的调控作用。这些发现从表观遗传学的角度为进一步深入研究脂质代谢紊乱发病的潜在分子机制提供了依据,为相关疾病的卫生预防、分子诊断和治疗提供参考。     

果蝇模型在研究铁代谢相关神经退行性疾病发病机制中的应用(英文)

铁代谢紊乱一直被视为是许多神经退行性疾病共同的病理特征,如阿尔茨海默氏症(Alzheimer’s disease,AD)、帕金森氏病(Parkinson’s disease,PD)以及弗里德赖希共济失调(Friedreich’s ataxia,FRDA)等均与脑铁代谢紊乱密切相关。随着分子生物学的进展,迄今为止也已经发现许多参与铁运输、储存和调控的基因与神经退行性病变的发生和发展有关,然而铁代谢紊乱在疾病发病过程中的致病机制仍不十分清楚。近年来许多研究者利用各种转基因动物模型来研究铁代谢相关神经退行性疾病的发病机制,但是啮齿类动物模型由于模型构建系统周期较长且比较复杂,从而限制了铁相关蛋白在神经退行性疾病中作用机制的研究进展。果蝇具有生活周期短暂、染色体数目少以及表型易于观察等优点,同时果蝇与人在很多基因和通路上都高度保守,且神经系统也可表现出与人相似的复杂的功能,因此被广泛地应用在铁代谢相关神经退行性疾病发病机制的研究中。果蝇还以其独特的分子遗传学优势,更容易构建缺失、插入、敲除或转基因模型,可在不同神经退行性病理情况下进行遗传学筛选铁相关的调控基因,从而为解决铁代谢紊乱在疾病发病过程中的致病机制提供更多的线索。因此在果蝇模型中发现可以中止甚至是逆转神经元退化进程的铁相关基因,以期为神经退行性疾病的研究和治疗提供策略。     

胆汁酸受体FXR 的研究进展

法尼酯衍生物X受体(FXR)是一种胆汁酸受体,在胆汁酸代谢和胆固醇代谢中发挥重要作用,并有望成为降低胆固醇,治疗某些心血管病及肝脏疾病的治疗靶点。本文介绍了FXR的发现、FXR在调控胆汁酸和脂质代谢中的作用,以及FXR在心血管疾病治疗中的应用前景。     

我国科学家揭示胆固醇吸收的分子机制及降胆固醇药物“益适纯”的作用原理

高胆固醇血症直接引起动脉粥样硬化,最终导致冠心病和脑中风等致死、致残性疾病。随着饮食结构的改变,目前从食物中摄取的过多脂质己成为诱发上述心脑血管疾病的主要致病因素。阐明胆固醇吸收的分子机制将为防治这类疾病提供重要基础。     

调控胆固醇吸收的分子通路

机体内的胆固醇失衡会引发多种疾病,如高胆固醇血症、心脑血管疾病等,而其平衡由胆固醇的合成、吸收、代谢和循环共同维持,其中胆固醇的吸收至关重要。胆固醇的吸收主要发生在小肠和近段空肠,受众多蛋白的调控。尼曼-匹克C1样蛋白1(NPC1L1)负责胆固醇的摄取;ATP结合盒转运蛋白(ABCG5/ABCG8)则抑制胆固醇的吸收,酰基辅酶A-胆固醇酰基转移酶(ACAT)催化胆固醇脂化提高胆固醇吸收;ATP结合盒转运蛋白A1(ABCA1)负责外周组织胆固醇的转运,而这些蛋白又受到其他调控因子的影响。解析胆固醇吸收的分子通路对胆固醇失衡相关疾病的预防及治疗具有重大指导意义。因此,本文就调控胆固醇吸收的分子通路进行综述。     

中草药调脂作用及其机制研究进展

高脂血症、动脉粥样硬化（ＡＳ）所致心脑血管疾病是危害人类健康的主要疾病之一。高脂血症又是ＡＳ发生首要危险因素,而脂代谢紊乱又与上述二者有着密切的关系。生物学技术、基因技术的不断应用,科研工作者对脂代谢紊乱从分子水平、细胞、亚细胞水平进行了大量研究。与...     

基于高密度脂蛋白代谢与重塑的抗动脉粥样硬化研究及相关药物

动脉粥样硬化（atherosclerosis,AS）是一种主要因血脂代谢紊乱引发的慢性炎症性血管疾病,以血管内膜下巨噬细胞和血管平滑肌细胞过度蓄脂泡沫化为主要病理特征。高密度脂蛋白（high-density lipoprotein,HDL）通过胆固醇逆向转运（reverse cholesterol transport,RCT）将外周细胞中的胆固醇运输到肝脏然后经胆汁排出体外,从而改善血脂水平和细胞的过度蓄脂,被认为是HDL抗AS的基础。然而,大量流行病学证据表明,虽然血浆高密度脂蛋白胆固醇（high-density lipoprotein cholesterol,HDL-C）水平与心血管风险呈负相关,但仅仅提高HDL-C水平的治疗策略不一定能增加临床效益。因此,学术界认识到HDL水平不足以反映其RCT能力,而更多取决于HDL功能。本文综述了参与调节HDL功能的各种分子对HDL代谢与重塑过程的影响,以及针对上述过程的相关药物研究进展,为更全面评价HDL的抗AS作用提供理论参考。     

Scavenger receptor Class B type I as a potential risk stratification biomarker and therapeutic target in cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of mortality globally. There are few useful markers available for CVD risk stratification that has proven clinical utility. Scavenger receptor B type I (SR-BI) is a cell surface protein that plays a major role in cholesterol homeostasis through its interaction with high-density lipoprotein-cholesterol (HDL-C) esters (CE). HDL delivers CE to the liver through selective uptake by the SR-BI. SR-BI also regulates the inflammatory response. It has been shown that SR-BI overexpression has beneficial, protective effects in atherogenesis, and there is considerable interest in developing antiatherogenic strategies that involve SR-BI-mediated increases in reverse cholesterol transport through HDL and/or low-density lipoprotein. Further investigations are essential to explore the clinical utility of this approach. Moreover, there is growing evidence showing associations between genetic variants with modulation of SR-BI function that may, thereby, increase CVD risk. The aim of the current review was to provide an overview of the possible molecular mechanisms by which SR-BI may affect CVD risk, and the clinical implications of this, with particular emphasis on preclinical studies on genetic changes of SR-BI and CVD risk.     

The vascular implications of post-prandial lipoprotein metabolism

Impaired lipoprotein metabolism is one of the major aetiological factors for the pathogenesis of atherosclerosis and cardiovascular disease (CVD). Assessment is usually made in the fasting state, and particular attention is directed towards the measurement of the cholesterol content of both the low and high-density lipoprotein fractions. By comparison, a massive amount of lipid fluxes through the intra-vascular compartment during the post-prandial period. This has led to the hypothesis that atherosclerosis could be partially, or even predominantly, due to the pathological effects of this flux of post-prandial lipoproteins on the vessel wall. This justifies efforts to systematically study the relationship between the lipoprotein responses to food (particularly fat) ingestion and cardiovascular disease or its surrogate markers. This review will consider the mechanisms by which post-prandial metabolism might affect the risk of CVD. It will examine the evidence for and against such an association. It will also consider the practical and methodological issues that are likely to determine the future utility of post-prandial lipoprotein assessment.     

Cholesterol and benign prostate disease

The origins of benign prostatic diseases, such as benign prostatic hyperplasia (BPH) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), are poorly understood. Patients suffering from benign prostatic symptoms report a substantially reduced quality of life, and the relationship between benign prostate conditions and prostate cancer is uncertain. Epidemiologic data for BPH and CP/CPPS are limited, however an apparent association between BPH symptoms and cardiovascular disease (CVD) has been consistently reported. The prostate synthesizes and stores large amounts of cholesterol and prostate tissues may be particularly sensitive to perturbations in cholesterol metabolism. Hypercholesterolemia, a major risk factor for CVD, is also a risk factor for BPH. Animal model and clinical trial findings suggest that agents that inhibit cholesterol absorption from the intestine, such as the class of compounds known as polyene macrolides, can reduce prostate gland size and improve lower urinary tract symptoms (LUTS). Observational studies indicate that cholesterol-lowering drugs reduce the risk of aggressive prostate cancer, while prostate cancer cell growth and survival pathways depend in part on cholesterol-sensitive biochemical mechanisms. Here we review the evidence that cholesterol metabolism plays a role in the incidence of benign prostate disease and we highlight possible therapeutic approaches based on this concept.     

Genetic connections between neurological disorders and cholesterol metabolism

Cholesterol is an essential component of both the peripheral and central nervous systems of mammals. Over the last decade, evidence has accumulated that disturbances in cholesterol metabolism are associated with the development of various neurological conditions. In addition to genetically defined defects in cholesterol synthesis, which will be covered in another review in this Thematic Series, defects in cholesterol metabolism (cerebrotendinous xanthomatosis) and intracellular transport (Niemann Pick Syndrome) lead to neurological disease. A subform of hereditary spastic paresis (type SPG5) and Huntington''s disease are neurological diseases with mutations in genes that are of importance for cholesterol metabolism. Neurodegeneration is generally associated with disturbances in cholesterol metabolism, and presence of the E4 isoform of the cholesterol transporter apolipoprotein E as well as hypercholesterolemia are important risk factors for development of Alzheimer''s disease. In the present review, we discuss the links between genetic disturbances in cholesterol metabolism and the above neurological disorders.     

Markers of enhanced cholesterol absorption are a strong predictor for cardiovascular diseases in patients without diabetes mellitus

Objective

Hypercholesterolemia is a major risk factor for cardiovascular disease (CVD), and diabetes mellitus and statin treatment affect cholesterol metabolism. The aim of the present study was to evaluate markers of cholesterol metabolism and determine their relationship with CVD in patients without diabetes mellitus who were not receiving statin treatment.

Methods

In addition to conventional CVD risk factors, plasma levels of campesterol and sitosterol (indicators of cholesterol absorption) and lathosterol (an indicator of cholesterol synthesis) were determined in 835 consecutive patients referred for coronary angiography. Coronary artery disease was evaluated by coronary angiograms, carotid atherosclerosis and peripheral vascular disease were assessed by Doppler ultrasound, and cerebrovascular accidents and transient ischemic attacks were identified by medical history.

Results

After excluding patients with known diabetes mellitus and those receiving statin treatment, 177 patients were included in the analysis. Compared to patients without CVDs (n = 111), patients with concomitant CVDs (n = 66) had a reduced lathosterol-to-cholesterol ratio (1.25 ± 0.61 vs. 1.38 ± 0.63, P < 0.05) and an increased campesterol-to-cholesterol ratio (1.81 ± 1.04 vs. 1.50 ± 0.69, P < 0.05), indicating that enhanced absorption and reduced synthesis of cholesterol is associated with CVD development. Logistic regression analysis including all established cardiovascular risk factors (age, sex, total cholesterol, arterial hypertension, body mass index and smoking) revealed that campesterol and the campesterol-to-cholesterol ratio were significant predictors of concomitant CVD in this patient population.

Conclusion

In patients without diabetes mellitus, markers of enhanced cholesterol absorption were a strong predictor for concomitant CVD.     

Evaluation of HDL-modulating interventions for cardiovascular risk reduction using a systems pharmacology approach

The recent failures of cholesteryl ester transport protein inhibitor drugs to decrease CVD risk, despite raising HDL cholesterol (HDL-C) levels, suggest that pharmacologic increases in HDL-C may not always reflect elevations in reverse cholesterol transport (RCT), the process by which HDL is believed to exert its beneficial effects. HDL-modulating therapies can affect HDL properties beyond total HDL-C, including particle numbers, size, and composition, and may contribute differently to RCT and CVD risk. The lack of validated easily measurable pharmacodynamic markers to link drug effects to RCT, and ultimately to CVD risk, complicates target and compound selection and evaluation. In this work, we use a systems pharmacology model to contextualize the roles of different HDL targets in cholesterol metabolism and provide quantitative links between HDL-related measurements and the associated changes in RCT rate to support target and compound evaluation in drug development. By quantifying the amount of cholesterol removed from the periphery over the short-term, our simulations show the potential for infused HDL to treat acute CVD. For the primary prevention of CVD, our analysis suggests that the induction of ApoA-I synthesis may be a more viable approach, due to the long-term increase in RCT rate.     

Effects of transdermal estrogen on levels of lipids, lipase activity, and inflammatory markers in men with prostate cancer

Androgen deprivation therapy (ADT) for prostate cancer is now used in earlier disease stages and as adjuvant treatment. Recognizing and reducing the toxicity of this therapy, including worsened lipid levels and cardiovascular disease (CVD) risks, has become an important clinical concern. Oral estrogen therapy induces hypogonadism and mitigates many side effects of ADT, but has a high thrombosis risk. Transdermal estrogen therapy (TDE) has a lower thrombosis risk than oral estrogen and may improve CVD risk compared with ADT. This prospective pilot study of 18 men with androgen-independent prostate cancer receiving ADT measured effects of TDE on lipid and inflammatory CVD risk factors before and after 8 weeks of TDE (estradiol 0.6 mg/day). During treatment, estradiol levels rose 17-fold; total cholesterol, LDL cholesterol, and apolipoprotein B levels decreased. HDL2 cholesterol increased, with no changes in triglyceride or VLDL cholesterol levels. Dense LDL cholesterol decreased and LDL buoyancy increased in association with a decrease in HL activity. Highly sensitive C-reactive protein levels and other inflammatory markers did not worsen. Compared with ADT, short-term TDE therapy of prostate cancer improves lipid levels without deterioration of CVD-associated inflammatory markers and may, on longer-term follow-up, improve CVD and mortality rates.     

Mitotic Spindle Defects and Chromosome Mis-Segregation Induced by LDL/Cholesterol—Implications for Niemann-Pick C1, Alzheimer’s Disease,and Atherosclerosis

Elevated low-density lipoprotein (LDL)-cholesterol is a risk factor for both Alzheimer’s disease (AD) and Atherosclerosis (CVD), suggesting a common lipid-sensitive step in their pathogenesis. Previous results show that AD and CVD also share a cell cycle defect: chromosome instability and up to 30% aneuploidy–in neurons and other cells in AD and in smooth muscle cells in atherosclerotic plaques in CVD. Indeed, specific degeneration of aneuploid neurons accounts for 90% of neuronal loss in AD brain, indicating that aneuploidy underlies AD neurodegeneration. Cell/mouse models of AD develop similar aneuploidy through amyloid-beta (Aß) inhibition of specific microtubule motors and consequent disruption of mitotic spindles. Here we tested the hypothesis that, like upregulated Aß, elevated LDL/cholesterol and altered intracellular cholesterol homeostasis also causes chromosomal instability. Specifically we found that: 1) high dietary cholesterol induces aneuploidy in mice, satisfying the hypothesis’ first prediction, 2) Niemann-Pick C1 patients accumulate aneuploid fibroblasts, neurons, and glia, demonstrating a similar aneugenic effect of intracellular cholesterol accumulation in humans 3) oxidized LDL, LDL, and cholesterol, but not high-density lipoprotein (HDL), induce chromosome mis-segregation and aneuploidy in cultured cells, including neuronal precursors, indicating that LDL/cholesterol directly affects the cell cycle, 4) LDL-induced aneuploidy requires the LDL receptor, but not Aß, showing that LDL works differently than Aß, with the same end result, 5) cholesterol treatment disrupts the structure of the mitotic spindle, providing a cell biological mechanism for its aneugenic activity, and 6) ethanol or calcium chelation attenuates lipoprotein-induced chromosome mis-segregation, providing molecular insights into cholesterol’s aneugenic mechanism, specifically through its rigidifying effect on the cell membrane, and potentially explaining why ethanol consumption reduces the risk of developing atherosclerosis or AD. These results suggest a novel, cell cycle mechanism by which aberrant cholesterol homeostasis promotes neurodegeneration and atherosclerosis by disrupting chromosome segregation and potentially other aspects of microtubule physiology.     

Assessing the mechanisms of cholesteryl ester transfer protein inhibitors

Cholesteryl ester transfer protein (CETP) inhibitors are a new class of therapeutics for dyslipidemia that simultaneously improve two major cardiovascular disease (CVD) risk factors: elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol. However, the detailed molecular mechanisms underlying their efficacy are poorly understood, as are any potential mechanistic differences among the drugs in this class. Herein, we used electron microscopy (EM) to investigate the effects of three of these agents (Torcetrapib, Dalcetrapib and Anacetrapib) on CETP structure, CETP-lipoprotein complex formation and CETP-mediated cholesteryl ester (CE) transfer. We found that although none of these inhibitors altered the structure of CETP or the conformation of CETP-lipoprotein binary complexes, all inhibitors, especially Torcetrapib and Anacetrapib, increased the binding ratios of the binary complexes (e.g., HDL-CETP and LDL-CETP) and decreased the binding ratios of the HDL-CETP-LDL ternary complexes. The findings of more binary complexes and fewer ternary complexes reflect a new mechanism of inhibition: one distal end of CETP bound to the first lipoprotein would trigger a conformational change at the other distal end, thus resulting in a decreased binding ratio to the second lipoprotein and a degraded CE transfer rate among lipoproteins. Thus, we suggest a new inhibitor design that should decrease the formation of both binary and ternary complexes. Decreased concentrations of the binary complex may prevent the inhibitor was induced into cell by the tight binding of binary complexes during lipoprotein metabolism in the treatment of CVD.